142 Records downloaded - Fri Feb 23 20:25:46 UTC 2018 RECORD 1 TITLE Human endogenous retroviruses differentially regulate immune checkpoints and modulation of immune responses in serous ovarian carcinoma AUTHOR NAMES Strissel P.L. Chiappinelli K.B. Strehl J. Würfel F.M.B. Beckmann M.W. Baylin S.B. Strick R. AUTHOR ADDRESSES (Strissel P.L.; Strehl J.; Würfel F.M.B.; Beckmann M.W.; Strick R.) Institute for Pathology, University-Clinic, Erlangen, Germany. (Chiappinelli K.B.; Baylin S.B.) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States. CORRESPONDENCE ADDRESS P.L. Strissel, Institute for Pathology, University-Clinic, Erlangen, Germany. SOURCE Cancer Immunology Research (2017) 5:3 Supplement 1. Date of Publication: 1 Mar 2017 CONFERENCE NAME AACR Special Conference on Tumor Immunology and Immunotherapy 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-10-20 to 2016-10-23 ISSN 2326-6074 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Purpose: The first aim is to investigate the activation of 7 immune checkpoints at different time points following transfection of three diverse ERV envelope (env) genes in serous ovarian carcinoma cells. The second aim is to determine if the ERV-W1 Syncytin-1 env and ERV-3 protein are expressed in primary serous OvCa tumors and ascites fluids to explore a possible role in the tumor microenvironment. Introduction: The overall survival of serous OvCa has not greatly improved. We and others have demonstrated up-regulation of interferon (IFN) type I signaling pathway viral defense genes including IFN stimulated genes (ISGs), in a variety of human tumors (ovary, breast, lung) but also in ovarian and colon carcinoma cell lines treated with the DNA methyltransferase inhibitor Aza-C. Aza-C treatment of serous OvCa cell lines leads to an induction of PD-L1 expression as mediated downstream signaling via IFNg. We recently demonstrated that activated ERVs function at the RNA level to ignite the IFN response. Exogenous retroviruses like HIV have evolved to suppress the immune response by up-regulation of PD-L1 on target cells. Tumors mimic regulatory mechanisms involving immunosuppression and inflammation, which we propose involves ERVs. Experimental Procedures: ERV-3, Syncytin-1 and ERV-W2 env CMV overexpression vectors and a control EGFP-vector were transfected into OvCa serous cell lines (TykNu, A2780 and Hey) and RNA expression of 7 immune checkpoint molecules (LGALS9, PDL-2, CD80, CD276, PD-L1, VTCN1 and PD1) were monitored at days 3 and 7 post transfection using real time PCR. Immunohistochemistry (IHC) and Western analyses using antibodies for Syncytin-1 and ERV-3 were performed with primary serous OvCa tumors. Western and ELISA analyses of serous OvCa ascites were executed to detect Syncytin-1 protein levels. Syncytin-1 protein concentrations were quantified in ascites with two different antibodies using ELISA and correlated to a standard curve based on purified Syncytin-1 levels. Results: Three serous OvCa cell lines following ERV env transfection showed differences of immune checkpoint activation. TykNu demonstrated the highest fold-levels of induction for LGALS9 (73.1x), PD-L1 (15.2x), PD-L2 (9.8x) and PD1 (6.1x) at day 3 for all ERV expression vectors, which decreased by day 7 except for PD1. A2780 showed increased levels for LGALS9 (7.2x) and PD1 (5.2x) with all ERV expression vectors at day 3, which decreased by day 7. In contrast, Hey cells showed no significant increase of the analyzed immune checkpoint genes. Syncytin-1 and ERV-3 protein was highly expressed in primary OvCa epithelial cells using IHC, compared to patient matched control ovarian tissues. Western analyses of ascites from OvCa patients showed high levels of Syncytin-1 in the supernatant, supporting protein secretion. Absolute quantification using real time PCR of Syncytin-1 and ERV-3 RNA with fractionated OvCa ascites cells demonstrated high amounts of molecules. ELISA results confirmed high levels of Syncytin-1 (98.6-525.8 microg/ml) in ascites of primary OvCa and in one relapse patient (413.4 microg/ml), but were virtually undetectable in an ascites from a gastro-intestinal carcinoma and control peritoneal fluids (2.7 microg/ml). Conclusions: Our findings that various immune checkpoints are differentially regulated following ERV activation in serous OvCa cell lines endorses that analyses of immune checkpoints prior to treatment could help stratify patient therapy. ERVs like exogenous retroviruses not only play an essential functional role at the RNA level via TLR3, but also possibly at the protein level via TLR4 modulation of immune/inflammatory responses. EMTREE DRUG INDEX TERMS antibody B7 antigen DNA methyltransferase inhibitor ecalectin endogenous compound interferon programmed death 1 ligand 1 toll like receptor 3 toll like receptor 4 V set domain containing T cell activation inhibitor 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) endogenous retrovirus immunomodulation ovary carcinoma EMTREE MEDICAL INDEX TERMS adult ascites cell ascites fluid breast cancer recurrence cancer survival colon carcinoma cell line conference abstract controlled study envelope gene enzyme linked immunosorbent assay epithelium cell expression vector female gene overexpression genetic transfection human human cell Human immunodeficiency virus human tissue immune response immunohistochemistry immunosuppressive treatment in vitro study inflammation lung nonhuman ovary tissue OVCA cell line overall survival peritoneal fluid protein secretion real time polymerase chain reaction relapse signal transduction supernatant target cell tumor microenvironment upregulation CAS REGISTRY NUMBERS toll like receptor 4 (203811-83-0) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L620636751 DOI 10.1158/2326-6074.TUMIMM16-A55 FULL TEXT LINK http://dx.doi.org/10.1158/2326-6074.TUMIMM16-A55 COPYRIGHT Copyright 2018 Elsevier B.V., All rights reserved. RECORD 2 TITLE Nivolumab related insulin-dependent diabetes AUTHOR NAMES Akturk H.K. Meek S. Joseph R. AUTHOR ADDRESSES (Akturk H.K.; Meek S.; Joseph R.) Jacksonville, United States. CORRESPONDENCE ADDRESS H.K. Akturk, Jacksonville, United States. SOURCE Diabetes (2016) 65 Supplement 1 (A414). Date of Publication: 2016 CONFERENCE NAME 76th Scientific Sessions of the American Diabetes Association, ADA 2016 CONFERENCE LOCATION New Orleans, LA, United States CONFERENCE DATE 2016-06-10 to 2016-06-14 ISSN 1939-327X BOOK PUBLISHER American Diabetes Association Inc. ABSTRACT New immunotherapy medications are used for multiple cancers. Blocking inhibitory molecules on activated T cells can cause tumor destruction but also enable pathological T cell to react with self-antigens. Only a couple cases have been reported for the possible link between CTLA-4, PD-1 monoclonal antibodies and autoimmune diabetes. We report a case that developed insulin-dependent diabetes with diabetic ketoacidosis after Nivolumab therapy. A 70-year-old male presented with nausea, vomiting and altered mental status. On arrival, he was tachycardic otherwise vitals were normal. Physical exam showed upper abdominal tenderness. He has a history of stage 4 renal cell cancer and Nivolumab was started six weeks ago. His last Nivolumab dose was two days ago and he had received a total of three doses, which were administered every other week at a dose of 300 mg IV. There was no family history of diabetes and his blood glucose and HbA1c were normal at his previous visit months prior to admission. Laboratory exam showed his serum glucose was 778 mg/dl; creatinine was 2.5 mg/ dl, urine ketones and blood acetones were positive; thyroid function tests were normal. Anion gap was 25, bicarbonate was 14, potassium was 4.2 mEq/L and sodium was 125 mEq/L. Anti-GAD65 antibodies were negative. C-peptide was low (0.4 ng/ml). HbA1c was 8.4%. Amylase and lipase were normal. Abdomen CT showed previously seen stable peritoneal metastases however there was no metastases to liver or pancreas and there was no evidence of pancreatitis. The patient was diagnosed with diabetic ketoacidosis. IV hydration and insulin were initiated. The patient did well and was dismissed with a multiple daily insulin regimen after diabetes education. The most common endocrinopathies that are associated with CTLA-4 and PD-1 inhibitors are hypophysitis and thyroiditis. They were often permanent. New onset diabetes is rare however physicians should be aware of the risk of insulin-dependent diabetes in patients that are treated with PD-1 monoclonal antibodies, especially with Nivolumab. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS amylase bicarbonate C peptide creatinine cytotoxic T lymphocyte antigen 4 endogenous compound glutamate decarboxylase 65 antibody hemoglobin A1c insulin potassium programmed death 1 receptor sodium triacylglycerol lipase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) insulin dependent diabetes mellitus EMTREE MEDICAL INDEX TERMS abdomen abdominal tenderness adverse drug reaction aged anion gap cancer staging case report diabetes education diabetic ketoacidosis diagnosis drug therapy family history glucose blood level human hydration hypophysitis ketonuria liver low drug dose male mental health nausea and vomiting pancreatitis peritoneum metastasis physical examination physician renal cell carcinoma risk assessment side effect tachycardia thyroid function test thyroiditis CAS REGISTRY NUMBERS amylase (9000-90-2, 9000-92-4, 9001-19-8) bicarbonate (144-55-8, 71-52-3) C peptide (59112-80-0) creatinine (19230-81-0, 60-27-5) hemoglobin A1c (62572-11-6) insulin (9004-10-8) nivolumab (946414-94-4) potassium (7440-09-7) sodium (7440-23-5) triacylglycerol lipase (9001-62-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L620238919 DOI 10.2337/db16-1375-1656 FULL TEXT LINK http://dx.doi.org/10.2337/db16-1375-1656 COPYRIGHT Copyright 2018 Elsevier B.V., All rights reserved. RECORD 3 TITLE Association between thyroid dysfunction and progression-free survival in patients with non-small cell lung cancer received nivolumab AUTHOR NAMES Funazo T. Ozasa H. Nomizo T. Yasuda Y. Tsuji T. Yoshida H. Sakamori Y. Nagai H. Hirai T. Kim Y. AUTHOR ADDRESSES (Funazo T.; Ozasa H.; Nomizo T.; Yasuda Y.; Tsuji T.; Yoshida H.; Sakamori Y.; Nagai H.; Hirai T.; Kim Y.) Respiratory Medicine, Kyoto University, Kyoto, Japan. CORRESPONDENCE ADDRESS T. Funazo, Respiratory Medicine, Kyoto University, Kyoto, Japan. SOURCE Journal of Thoracic Oncology (2017) 12:11 Supplement 2 (S2421-S2422). Date of Publication: 1 Nov 2017 CONFERENCE NAME 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, IASLC 2017 CONFERENCE LOCATION Yokohama, Japan CONFERENCE DATE 2017-10-15 to 2017-10-18 ISSN 1556-1380 BOOK PUBLISHER Elsevier Inc. ABSTRACT Background: Nivolumab is one of immune-checkpoint inhibitors and has the first agent approved by the U.S. Food and Drug Administration for advanced non-small cell lung cancer (NSCLC). However, the rate of objective responses remains at approximately 20%.Additionally, immune-checkpoint inhibitors often have developed immune-related adverse events. We have previously reported that PD-L1 single nucleotide polymorphisms (SNPs) were possible biomarker for efficacy of nivolumab. We investigated the association between genetic polymorphisms in the PD-1/PD-L1 gene and clinical outcome for nivolumab including response and adverse events. Method: A total of 68 consecutive patients with NSCLC were treated with nivolumab from December 2015 to October 2016 at Kyoto University. Of these patients, 59 participated in the present study. The remaining 9 patients were excluded from this study because 3 patients declined informed consent, 2 patients had no follow up blood examination, one patient had a history of double cancer and 4 patients had determined as progression disease within 15days from the first administration of nivolumab. Seven SNPs (PD-L1; rs822339, rs1411262, rs2890658, rs4143815, rs2282055, PD-1; rs2227981, rs2227982) were genotyped using TaqMan genotyping assay. Response was assessed as per the Response Evaluation Criteria in Solid Tumors (version 1.1) by investigators respectively. Adverse events were assessed as per the Common Terminology Criteria for Adverse Events (version 4.0) by an investigator. We defined hyperthyroidism as elevated FT4 or FT3 and hypothyroidism as low FT4.We explored the association of adverse events and the PD-1/PD-L1 SNPs subtypes using the Cochrane-Armitage test and Fisher's exact test as appropriate. Difference of progression free survival (PFS) between each group was assessed using the log-rank test. Result: Median PFS in this group was 67days (95% confidence interval, 54 to 107 days). Median PFS was significantly longer in patients with thyroid dysfunction than in those without thyroid dysfunction (152 vs 58 days; P = 0.0349). GG and GT genotype of rs2282055 were related to better PFS (82 vs 65 days; P = 0.0311). There were no significant association between thyroid dysfunction and SNPs. However, absence of thyroid dysfunction in patients with TT genotype of rs22282055 suggests that rs2282055 might be related thyroid dysfunction (P=0.1863 Fisher's exact test). Conclusion: In the patients treated with nivolumab, GG and GT genotype of rs2282055 might be a predictive biomarker for response and might contribute the occurrence of thyroid dysfunction. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS biological marker endogenous compound programmed death 1 ligand 1 programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer survival hyperthyroidism non small cell lung cancer progression free survival single nucleotide polymorphism EMTREE MEDICAL INDEX TERMS adult adverse event blood examination clinical outcome clinical trial controlled clinical trial controlled study drug therapy female follow up gene mutation genetic marker genetic susceptibility genotype human human tissue hypothyroidism informed consent log rank test major clinical study male nomenclature response evaluation criteria in solid tumors CAS REGISTRY NUMBERS nivolumab (946414-94-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L620148255 COPYRIGHT Copyright 2018 Elsevier B.V., All rights reserved. RECORD 4 TITLE Thyroid dysfunction arising during keynote-001 associated with improved efficacy of pembrolizumab in NSCLC patients at UCLA AUTHOR NAMES Lisberg A. Bornazyan K. Madrigal J. Bui J. Carroll J. Adame C. Hunt J. Lu H. Noor Z. Cummings A. Goldman J.W. Garon E. AUTHOR ADDRESSES (Lisberg A.; Bornazyan K.; Madrigal J.; Bui J.; Carroll J.; Adame C.; Hunt J.; Lu H.; Noor Z.; Cummings A.; Goldman J.W.; Garon E.) University of California, Los Angeles, United States. CORRESPONDENCE ADDRESS A. Lisberg, University of California, Los Angeles, United States. SOURCE Journal of Thoracic Oncology (2017) 12:11 Supplement 2 (S2430). Date of Publication: 1 Nov 2017 CONFERENCE NAME 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, IASLC 2017 CONFERENCE LOCATION Yokohama, Japan CONFERENCE DATE 2017-10-15 to 2017-10-18 ISSN 1556-1380 BOOK PUBLISHER Elsevier Inc. ABSTRACT Background: PD-1/PD-L1 blockade has rapidly been adopted for treatment of NSCLC. However, much remains to be learned about the implications of the side-effect profile of PD-1/PD-L1 blockade. We previously showed that the 38 patients who experienced a treatment related AE (trAE) on the KEYNOTE-001 trial at UCLA had superior clinical outcomes compared to the 59 that did not. Treatment related hypothyroidism was the most predictive trAE for response to therapy [objective response rate (ORR): 83.3% (5/6 patients with response)]. The highly predictive nature of treatment related hypothyroidism led us to further evaluate the implications of thyroid dysfunction in our patient cohort by analyzing the association between therapeutic efficacy and thyroid specific laboratory values obtained on trial. Method: We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 12/2016). Patients had Thyroid Stimulating Hormone (TSH), free Thyroxine 4 (fT4), and Triiodothyronine (T3) assessed at baseline (prior to therapy), cycle 2, and every other cycle thereafter. In some instances, labs were obtained at safety followup and unscheduled visits. Tumor response was evaluated using investigator assessed immune related response criteria (irRC), with imaging q9wks. Result: 97.9% (95/97) of the patients treated at UCLA on KEYNOTE-001 had a baseline set of thyroid indices, while 74.7% (68/97) had ≥3 sets of values. Patients with an abnormal TSH during study participation had a higher ORR, 35.5% (11/31), than those that did not, 14.1% (9/64) (p=0.0296), with an acquired TSH abnormality (first observed after C1D1) more predictive of response than a baseline abnormality [acquired TSH abnormality: ORR 42.9% (9/21) vs baseline abnormality: ORR 20% (2/10)]. An abnormal fT4 or abnormal T3 on trial were also both independently associated with improved response to therapy [fT4 abnormality+: ORR: 50% (5/10) vs fT4 abnormality-: 17.7% (15/85) (p=0.0317) and T3 abnormality+: ORR 47.4% (9/19) vs T3 abnormality-: ORR 14.5% (11/76) (p=0.0037)]. As with TSH, acquired fT4 and T3 abnormalities were associated with higher ORR than baseline abnormalities. Conclusion: Thyroid dysfunction, assessed by abnormalities in TSH, fT4, or T3, was associated with improved efficacy of pembrolizumab on the KEYNOTE-001 trial at UCLA and an acquired thyroid abnormality, defined as first occurrence after C1D1, was more predictive of improved efficacy than a baseline abnormality. Future work is ongoing to evaluate this association in a larger patient population and molecular mechanisms that may be underlying this observation. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab programmed death 1 receptor EMTREE DRUG INDEX TERMS endogenous compound liothyronine thyrotropin thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypothyroidism non small cell lung cancer EMTREE MEDICAL INDEX TERMS adult clinical trial congenital malformation drug therapy female follow up human immune-related gene major clinical study male retrospective study treatment response CAS REGISTRY NUMBERS liothyronine (6138-47-2, 6893-02-3) pembrolizumab (1374853-91-4) thyrotropin (9002-71-5) thyroxine (7488-70-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L620147388 COPYRIGHT Copyright 2018 Elsevier B.V., All rights reserved. RECORD 5 TITLE Thyroid disfunction in advanced NSCLC patients treated with nivolumab out of clinical trial: A real-world data analysis AUTHOR NAMES Palmero R. Ruffinelli J.C. Alanya E. Marin J.A. Ferrer M. Jove M. Mesia C. Arellano M. Brao I. Cardenal F. Peiro I. Nadal E. AUTHOR ADDRESSES (Palmero R.; Ruffinelli J.C.; Alanya E.; Marin J.A.; Jove M.; Mesia C.; Arellano M.; Brao I.; Cardenal F.; Nadal E.) Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet, Spain. (Ferrer M.) Medical Oncology, Hospital Moises Broggi, Catalan Institute of Oncology, Sant Joan Despi, Spain. (Peiro I.) Department of Endocrinology and Nutrition, Hospital de Bellvitge, L' Hospitalet de Llobregat, Spain. CORRESPONDENCE ADDRESS R. Palmero, Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet, Spain. SOURCE Journal of Thoracic Oncology (2017) 12:11 Supplement 2 (S2432). Date of Publication: 1 Nov 2017 CONFERENCE NAME 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, IASLC 2017 CONFERENCE LOCATION Yokohama, Japan CONFERENCE DATE 2017-10-15 to 2017-10-18 ISSN 1556-1380 BOOK PUBLISHER Elsevier Inc. ABSTRACT Background: Immune-related adverse events occur in a subset of patients (pts) treated with immune checkpoint inhibitors blocking PD1/PD-L1 interaction. It has been reported that NSCLC pts treated with pembrolizumab who developed thyroid dysfunction (TD) had better clinical outcome. In this retrospective study, we examined the prognostic value of TD in advanced NSCLC pts treated with nivolumab. Method: Ninety-seven pts with advanced NSCLC treated with nivolumab in second and latter lines out of clinical trial at the Institut Català d'Oncologia (Barcelona, Spain) between November 2015 and March 2017 were included in this analysis. Thyroid tests were assessed at baseline and at the clinician's discretion during treatment. TD was defined as abnormal levels of TSH value during nivolumab treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Result: Of 97 pts, most patients received nivolumab in second line (73%). The median age was 63 years (38-82), most were men (76%), former or active smokers (87%), with adenocarcinoma (59%) or squamous cell carcinoma (31%), and had good performance status (88% ECOG PS 0-1). With a median follow-up of 8 months, 42 (43%) patients had died and 60 (62%) presented progressive disease. Sixteen pts (16.5%) developed TD that was G1 (9, 56%) or G2 (7, 44%). Two pts who developed G2 hyperthyroidism required steroid treatment and 5 pts who developed G2 hypothyroidism received substitutive hormone therapy. Median time until TD was 41 days (95% CI 37-45) and pts with TD received more cycles of nivolumab compared with euthyroid pts (11.5 versus 4, respectively). Pts with TD were more likely to achieve a tumor response compared to euthyroid pts (44% versus 14%, p=0.13). Median PFS and OS were significantly longer in pts who developed thyroid dysfunction compared with euthyroid pts. Median PFS was 3.7 months in euthyroid pts vs NR in pts with TD (p=0.001; odds ratio, 0.14; 95% CI 0.04-0.48) and median OS was 8.1 months vs NR, respectively (p=0.005; odds ratio, 0.15; 95% CI 0.03-0.69). Conclusion: This realworld data analysis showed that treatment-related TD predicts favorable clinical outcome from nivolumab in advanced NSCLC pts. A comprehensive analysis of thyroid stimulating hormone (TSH) kinetics will be presented at the meeting. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS endogenous compound pembrolizumab steroid thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adverse event data analysis immune-related gene non small cell lung cancer EMTREE MEDICAL INDEX TERMS adenocarcinoma adult cancer prognosis cancer survival cell cycle G1 phase clinical outcome clinical trial controlled clinical trial controlled study drug therapy follow up gene expression hormonal therapy human hyperthyroidism hypothyroidism Kaplan Meier method kinetics major clinical study male middle aged overall survival progression free survival retrospective study smoking Spain squamous cell carcinoma CAS REGISTRY NUMBERS nivolumab (946414-94-4) pembrolizumab (1374853-91-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L620147635 COPYRIGHT Copyright 2018 Elsevier B.V., All rights reserved. RECORD 6 TITLE A phase II study of pembrolizumab for patients with refractory or relapsed thymic epithelial tumor AUTHOR NAMES Cho J. Yoo K.H. Lee H. Kim H.K. Kim Y. Cho J.H. Lim S.W. Park S.E. Sun J. Lee S. Ahn J.S. Park K. Ahn M. AUTHOR ADDRESSES (Cho J.) Inha University Hospital, Incheon, South Korea. (Yoo K.H.; Lee H.; Kim H.K.; Kim Y.; Cho J.H.; Lim S.W.; Park S.E.; Sun J.; Lee S.; Ahn J.S.; Park K.; Ahn M.) Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, South Korea. CORRESPONDENCE ADDRESS J. Cho, Inha University Hospital, Incheon, South Korea. SOURCE Journal of Thoracic Oncology (2017) 12:11 Supplement 2 (S1749-S1750). Date of Publication: 1 Nov 2017 CONFERENCE NAME 18th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer, IASLC 2017 CONFERENCE LOCATION Yokohama, Japan CONFERENCE DATE 2017-10-15 to 2017-10-18 ISSN 1556-1380 BOOK PUBLISHER Elsevier Inc. ABSTRACT Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with refractory or relapsed TET to evaluate the efficacy and safety. Method: Between March 2016 and June 2017, patients with histologically confirmed TET who progressed after at least one platinum- containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year or documented history of clinically severe autoimmune disease. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. Response was assessed every 9 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT02607631. Result: Thirty-three patients were enrolled, 26 with thymic carcinoma and 7 with thymoma. 19 (57.3%) patients received two or more prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-22) and median follow-up was 11.8 months (ranges, 1.6-14.9 months). Of 33 patients, eight (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was 6.1 months for both of thymoma and thymic carcinoma. The most common adverse events of any grade include dyspnea (11 [33.3%] of 33 patients), chest wall pain (10 [30.3%]), anorexia (7 [21.2%]) and fatigue (7 [21.2%]). Treatmentrelated adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (4 [12.1%]), myocarditis (3 [9.1%]), myasthenia gravis (2 [6.1%]), thyroiditis (1 [3.0%]), ANCA-associated rapidly progressive glomerulonephritis (1 [3.0%]), colitis (1 [3.0%]), and subacute myoclonus (1 [3.0%]) except anemia (1 [3.0%]). Eight (24.2%) patients (5 thymoma, 3 thymic carcinoma) discontinued study treatment due to irAE, whereas irAEs were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (7 of 8 [87.5%]). In 18 (54.5%) patients who had tumor specimens available for correlative biomarker analysis, all of four patients achieved partial response had 50% or more proportion score of PD-L1 immunostaining and higher PD-L1 RNA expression compared with non-responders (p=0.0471). Conclusion: Pembrolizumab showed promising antitumor activity in patients with refractory or relapsed TET. Given the relatively high incidence of irAEs especially in thymoma, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS biological marker corticosteroid endogenous compound immunosuppressive agent neutrophil cytoplasmic antibody platinum programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer recurrence carcinoma thymoma EMTREE MEDICAL INDEX TERMS adult adverse drug reaction anemia anorexia antineoplastic activity autoimmune disease cancer survival chemotherapy clinical article clinical trial colitis comparative effectiveness controlled clinical trial controlled study drug megadose drug therapy dyspnea fatigue feasibility study female follow up gene expression hepatitis human human tissue immune-related gene immunohistochemistry incidence male myasthenia gravis myocarditis myoclonus pain pharmacokinetics phase 2 clinical trial progression free survival rapidly progressive glomerulonephritis side effect systemic therapy thorax wall thyroiditis toxicity tumor growth CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L620148007 COPYRIGHT Copyright 2018 Elsevier B.V., All rights reserved. RECORD 7 TITLE Pembrolizumab (anti-PD-1) in a patient with recurrent granulosa cell tumor: A case-report AUTHOR NAMES Bekos C. Dekan S. Woitek R. Häusler G. Grimm C. Reinthaller A. Polterauer S. AUTHOR ADDRESSES (Bekos C.) AKH Wien, Department of General Gynaecology and Gynaecological Oncology, Vienna, Austria. (Dekan S.) Medical University Vienna, Department of Pathology, Vienna, Austria. (Woitek R.) Medical University Vienna, Department of Radiology, Vienna, Austria. (Häusler G.; Grimm C.; Reinthaller A.) Medical University Vienna, Department of General Gynaecology and Gynaecological Oncology, Vienna, Austria. (Polterauer S.) Department of General Gynaecology and Gynaecological Oncology, Vienna, Austria. CORRESPONDENCE ADDRESS C. Bekos, AKH Wien, Department of General Gynaecology and Gynaecological Oncology, Vienna, Austria. SOURCE International Journal of Gynecological Cancer (2017) 27 Supplement 4 (1432). Date of Publication: 1 Nov 2017 CONFERENCE NAME 20th International Meeting of the European Society of Gynaecological Oncology CONFERENCE LOCATION Vienna, Austria CONFERENCE DATE 2017-11-04 to 2017-11-07 ISSN 1525-1438 BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Aims Immuntherapies or Checkpoint inhibitors, targeting programmed cell death protein-1 (PD-1) and cytotoxic t-lymphocyte-associated antigen-4 (CTLA-4), could improve therapeutical outcomes of several malignant diseases. This is a report about the use of an anti-PD-1 antibody in a recurrent and unresectable granulosa cell tumor. Method In 2012, when our patient was 35 years old, a suspicious ovarian cancer was diagnosed during pregnancy. An unilateral adnexextirpation was performed laparoscopically within the pregnancy. During caesarean section an intraabdominal recurrence was diagnosed. By resection of the spleen, left adrenal gland, both diaphragms, liver segments II, II and part of segment VIII, R0 resection could be achieved. This was followed by four cycles of Bleomycin, Etoposid and Cisplatin. After that there was no more tumor traceable anymore. In July 2014, a tumor recurrence in the hilum of the liver and peritoneal carcinomatosis was diagnosed. The patient received 33 cycles of anti-VEGF antibody bevacizumab and an anti-hormonal therapy with letrozol. Results In September 2016 a new unresectable hepatal relapse was diagnosed. Therefore an off-label therapy with pembrolizumab 200mg dosed every three weeks was initiated. Diagnostic workup performing CT scans was planned after 3 and 6 months to evaluate therapeutical response. In the first CT scan, three months later, progressive disease according to RECIST criteria was diagnosed. The results from the 6 months follow up will be presented at the conference. Conclusion This is the first report about the use of pembrolizumab in recurrent, non-resectable granulosa cell tumor. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab programmed death 1 receptor EMTREE DRUG INDEX TERMS bevacizumab bleomycin cisplatin endogenous compound etoposide vasculotropin antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) granulosa cell tumor EMTREE MEDICAL INDEX TERMS adrenal gland adult cancer recurrence cancer surgery carcinomatous peritonitis case report cesarean section diagnosis diaphragm DNA polymorphism drug combination drug therapy female follow up hormonal therapy human liver pregnancy relapse response evaluation criteria in solid tumors spleen x-ray computed tomography CAS REGISTRY NUMBERS bevacizumab (216974-75-3) bleomycin (11056-06-7, 9041-93-4) cisplatin (15663-27-1, 26035-31-4, 96081-74-2) etoposide (33419-42-0, 433304-61-1) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619745503 DOI 10.1097/01.IGC.0000527296.86225.87 FULL TEXT LINK http://dx.doi.org/10.1097/01.IGC.0000527296.86225.87 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 8 TITLE Avelumab in patients with metastatic adrenocortical carcinoma (mACC): Results from the JAVELIN solid tumor trial AUTHOR NAMES Le Tourneau C. Zarwan C. Hoimes C. Wong D.J. Bauer S. Wermke M. Grote H.J. Von Heydebreck A. Chin K. Gulley J. AUTHOR ADDRESSES (Le Tourneau C.) Department of Medical Oncology, Institut Curie, Paris, France. (Zarwan C.) Medical Oncology, Lahey Hospital and Medical Center, Burlington, United States. (Hoimes C.) Hematology and Oncology, Case Western Reserve University, University Hospitals Seidman Cancer Center, Cleveland, United States. (Wong D.J.) Department of Medicine, University of California, Los Angeles Medical Center, Los Angeles, United States. (Bauer S.) Department of Medical Oncology, University Hospital Essen Westdeutsches Tumorzentrum, Essen, Germany. (Wermke M.) Early Clinical Trial Unit, Universitätsklinikum Dresden, Dresden, Germany. (Grote H.J.) Oncology, Merck KGaA, Darmstadt, Germany. (Von Heydebreck A.) Biostatistics, Merck KGaA, Darmstadt, Germany. (Chin K.) Immune-Oncology, EMD Serono,Inc, Billerica, United States. (Gulley J.) Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States. CORRESPONDENCE ADDRESS C. Le Tourneau, Department of Medical Oncology, Institut Curie, Paris, France. SOURCE Annals of Oncology (2017) 28 Supplement 5 (v324). Date of Publication: 1 Sep 2017 CONFERENCE NAME 42nd ESMO Congress, ESMO 2017 CONFERENCE LOCATION Madrid, Spain CONFERENCE DATE 2017-09-08 to 2017-09-12 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Avelumab is a human anti-PD-L1 IgG1 antibody that has shown promising clinical activity in multiple tumor types, and is approved in the US for the treatment of metastatic Merkel cell carcinoma. Here, we report an updated analysis of avelumab in patients (pts) with mACC, representing the largest prospective monotherapy study performed to date in this rare cancer with limited therapeutic options. Methods: In a phase 1b cohort (NCT01772004), pts with mACC and prior platinumbased therapy received avelumab at 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Prior and ongoing treatment with mitotane was permitted. Tumors were assessed every 6 wks (RECIST v1.1). Endpoints included safety (NCICTCAE v4.0), best overall response, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: As of Dec 31, 2016, 50 pts from 6 countries received avelumab for a median of 3.4 mos (0.5-24.8). Median follow-up was 16.5 mos (11.7-27.6); 5 pts (10.0%) remained on treatment. Median age was 50 y (range 21-71) and median time since diagnosis of metastatic disease was 14.5 mos. 24 pts (48.0%) had received ≥2 prior lines of treatment for advanced disease (median 1, range 0-6). 41 pts (82.0%) had a treatmentrelated adverse event (TRAE) of any grade; the most common (>15%) were nausea (20.0%) and fatigue (18.0%). 8 pts (16.0%) had a grade ≥3 TRAE, of which only increased ALT (4.0%) occurred in>1 pt. 12 pts (24.0%) had an immune-related AE of any grade. Confirmed ORR was 6.0%(3 partial responses; 95% CI 1.3-16.5); response was ongoing in 1 pt at data cutoff. 21 pts (42.0%) had stable disease as best response (disease control rate 48.0%). Median PFS was 2.6 mos (95% CI 1.4-4.0). Median OS was 10.6 mos (95% CI 7.4-not estimable) and the 12-mo OS rate was 47.0% (95% CI 31.8-60.9). Responses occurred in 2 pts with PD-L1+tumors and 1 PD-L1-(≥5% tumor cell cutoff). In PD-L1+(n=12) vs PD-L1-(n=30) subgroups, median PFS was 5.5 vs 1.7 mos (HR 0.66; 95% CI 0.3-1.4) and median OS was 14.4 vs 11.5 mos (HR 0.82; 95% CI 0.3-2.2), respectively. Conclusions: Avelumab had a manageable safety profile and demonstrated clinical activity in pts with platinum-treated mACC. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab EMTREE DRUG INDEX TERMS endogenous compound mitotane platinum programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal cortex carcinoma solid malignant neoplasm EMTREE MEDICAL INDEX TERMS adult adverse event cancer survival clinical article clinical trial cohort analysis controlled clinical trial controlled study diagnosis disease control drug therapy drug withdrawal fatigue female follow up human immune-related gene male metastasis middle aged monotherapy nausea overall survival pharmacokinetics progression free survival prospective study response evaluation criteria in solid tumors toxicity CAS REGISTRY NUMBERS avelumab (1537032-82-8) mitotane (53-19-0) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619624477 DOI 10.1093/annonc/mdx371.067 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx371.067 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 9 TITLE Pembrolizumab for patients with PD-L1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study AUTHOR NAMES Mehnert J.M. Rugo H.S. O'Neil B.H. Santoro A. Schellens J.H.M. Cohen R.B. Doi T. Ott P.A. Pishvaian M.J. Puzanov I. Aung K.L. Hsu C. Le Tourneau C. Soria J.-C. Elez E. Tamura K. Gould M. Zhao G. Stein K. Piha-Paul S.A. AUTHOR ADDRESSES (Mehnert J.M.) Phase I and Developmental Therapeutics Program, Rutgers Cancer Institute of New Jersey, New Brunswick, United States. (Rugo H.S.) Hematology/Oncology, UCSF Helen Diller Family, Comprehensive Cancer Center, San Francisco, United States. (O'Neil B.H.) Hematology/Oncology, Indiana University, Simon Cancer Center, Indianapolis, United States. (Santoro A.) Oncology, Humanitas Research Hospital-Humanitas Cancer Center, Rozzano, Italy. (Schellens J.H.M.) Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands. (Cohen R.B.) Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States. (Doi T.) Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan. (Ott P.A.) Medical Oncology, Dana-Farber Cancer Institute, Boston, United States. (Pishvaian M.J.) Lombardi Comprehensive Cancer Center, Georgetown University, Washington, United States. (Puzanov I.) Medicine, Roswell Park Cancer Institute, Buffalo, United States. (Aung K.L.) Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Net Work, Toronto, Canada. (Hsu C.) Oncology, National Taiwan University Hospital, Taipei, Taiwan. (Le Tourneau C.) Medical Oncology, Institut Curie, Paris, France. (Soria J.-C.) Drug Development, Gustave Roussy, Villejuif, France. (Elez E.) Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. (Tamura K.) Oncology, National Cancer Center Hospital, Tokyo, Japan. (Gould M.; Zhao G.; Stein K.) Clinical Research, Merck and Co., Inc., Kenilworth, United States. (Piha-Paul S.A.) Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, United States. CORRESPONDENCE ADDRESS J.M. Mehnert, Phase I and Developmental Therapeutics Program, Rutgers Cancer Institute of New Jersey, New Brunswick, United States. SOURCE Annals of Oncology (2017) 28 Supplement 5 (v142). Date of Publication: 1 Sep 2017 CONFERENCE NAME 42nd ESMO Congress, ESMO 2017 CONFERENCE LOCATION Madrid, Spain CONFERENCE DATE 2017-09-08 to 2017-09-12 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Among patients (pts) with advanced carcinoid/neuroendocrine tumors (NETs), expression of PD-L1 is associated with higher tumor grade. The multicohort phase 1b KEYNOTE-028 study (NCT02054806) evaluated safety and efficacy of pembrolizumab in pts with PD-L1-positive advanced solid tumors. This is the first report from the carcinoid and pancreatic NET (pNET) cohorts of this study. Methods: Eligibility criteria included: Carcinoid tumors or well- or moderately differentiated pNETs; PD-L1-positive (≥1% modified proportion score or interface pattern, QualTek IHC); failure of standard therapy; and ECOG PS≤1. Pts received pembrolizumab 10 mg/kg Q2W for up to 2 y or until confirmed progression, intolerable toxicity, or consent withdrawal. Response was assessed every 8 wk for 6mo then every 12 wk. The primary endpoint was ORR per RECIST v1.1 by investigator review. Results: 276 screened pts had tumor samples evaluable for PD-L1; 36% were positive. Among enrolled carcinoid (n=25 [lung, n=9; gut, n=7; other, n=9]) and pNET (n=16) pts, respectively, median ages were 63 y and 61 y, 76% and 38% had ECOG PS of 1, and 44% and 50% had ≥2 prior therapies for metastatic disease. As of Jan 10, 2017, median (range) follow up was 18.9 (2.0-33.3) and 20.1 (4.5-30.4) mo. Treatment-related AEs (TRAEs) occurred in 17 (68%) carcinoid and 11 (69%) pNET pts; the most frequent (≥20%) were diarrhea (n=7, 28%) and fatigue (n=5, 20%) in carcinoid pts and fatigue (n=6, 38%) and diarrhea (n=4, 25%) in pNET pts. Grade ≥3 TRAEs occurred in 8 (32%) carcinoid pts (including diarrhea, n=3; AST increased, n=2; ALT increased; n=2) and 0 pNET pts. One grade 4 AE (increased gammaglutamyl transferase) and 1 death (unspecified cause) occurred in the carcinoid cohort; neither was treatment related. Three carcinoid pts (12%; 95% CI, 3%-31%) and 1 pNET pt (6%; 95% CI, 0%-30%) had objective responses; SD rates were 60% (n=15) and 88% (n=14). Durations of response were 6.9, 9.2, and 11.1 mo for the carcinoid responders; the pNET responder has an ongoing response of 17.6 mo. Conclusions: In pts with heavily pretreated carcinoid/pNET tumors, pembrolizumab was generally well tolerated and, in some pts, provided clinically meaningful antitumor activity. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS endogenous compound gamma glutamyltransferase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) carcinoid disease course pancreas islet cell tumor EMTREE MEDICAL INDEX TERMS adult antineoplastic activity clinical trial death diarrhea drug therapy drug withdrawal fatigue female follow up gastrointestinal tract human human tissue immunohistochemistry lung major clinical study male metastasis middle aged pharmacokinetics phase 1 clinical trial response evaluation criteria in solid tumors toxicity treatment failure CAS REGISTRY NUMBERS gamma glutamyltransferase (85876-02-4) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619622707 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 10 TITLE N-DUR: Matched pair pharmacodynamics study of neoadjuvant durvalumab in combination with chemotherapy in frontline ovarian cancer AUTHOR NAMES Taylor J. Westin S. Sharafi S. Jazaeri A. Frumovitz M. Soliman P. Sood A. Lu K. Savelieva K. Mills G. Vergara-Silva A. Coleman R. AUTHOR ADDRESSES (Taylor J.; Westin S.; Sharafi S.; Jazaeri A.; Frumovitz M.; Soliman P.; Sood A.; Lu K.; Coleman R.) Gynecologic Oncology, MD Anderson Cancer Center, Houston, United States. (Savelieva K.; Mills G.) Systems Biology, MD Anderson Cancer Center, Houston, United States. (Vergara-Silva A.) MedImmune, Astra Zeneca, Gaithersburg, United States. CORRESPONDENCE ADDRESS J. Taylor, Gynecologic Oncology, MD Anderson Cancer Center, Houston, United States. SOURCE Annals of Oncology (2017) 28 Supplement 5 (v353-v354). Date of Publication: 1 Sep 2017 CONFERENCE NAME 42nd ESMO Congress, ESMO 2017 CONFERENCE LOCATION Madrid, Spain CONFERENCE DATE 2017-09-08 to 2017-09-12 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Although upfront treatment for ovarian cancer (OC) achieves complete remission in over 70% of women, the majority of patients (pts, 80%) relapse and die from disease. Thus, there is great interest in improving standard of care and exploring maintenance strategies. Immune evasion and suppression is a central feature of the OC microenvironment. Immune abrogation has also been linked to primary and adaptive chemoresistance and angiogenesis. Prolongation of immunocompetence represents a promising intervention to achieve lasting tumor suppression promoting survival. Further, chemotherapy may increase immunogenicity by releasing tumor-specific antigens providing an environment for long-term tumor control. Governance of T cell regulation with immune therapy has been explored in advanced solid tumors. Clinical experience with agents targeting PD-1/PD-L1 in OC is limited but responses have been observed. Durvalumab is a novel PD-L1 inhibitor with activity across a number of different solid tumors in in vitro and in vivo models. As yet, it is unknown which pts stand to benefit the most from this agent. Trial design: A total of 30 evaluable pts with untreated, advanced stage OC undergoing neoadjuvant chemotherapy will be treated with paclitaxel, carboplatin and durvalumab, followed by durvalumab maintenance. Pretreatment biopsies will be obtained at laparoscopy or by interventional radiology from up to 4 sites. Interval tumor reductive surgery (TRS) will be performed after 3 cycles. Matched biopsies will be obtained at TRS. The study incorporates a phase I safety lead in (n=6) to ensure the combination has acceptable toxicity and pts undergo TRS in a timely fashion. Dose-limiting toxicities (DLTs) will be assessed. This will be followed by open enrollment on the phase II portion. The primary objective is to explore basal levels and effects of durvalumab in combination with chemotherapy on molecular markers in immune-related pathways and lymphoid populations including DNA copy number, mutation, RNA/protein expression, PD-L1 expression and T-cell infiltration, before and after treatment. Secondary objectives are progression free survival, overall survival, and patient reported outcomes. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) durvalumab EMTREE DRUG INDEX TERMS carboplatin endogenous compound paclitaxel programmed death 1 ligand 1 programmed death 1 receptor tumor antigen EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) neoadjuvant chemotherapy ovary cancer pharmacodynamics EMTREE MEDICAL INDEX TERMS adult angiogenesis biopsy cancer control cancer inhibition cancer recurrence cancer staging cancer surgery cancer survival cell infiltration clinical article clinical trial drug combination drug resistance drug therapy drug toxicity female gene amplification gene expression genetic marker human human tissue immune evasion immune-related gene immunocompetence immunogenicity immunotherapy in vitro study in vivo study interventional radiology laparoscopy microenvironment mutation overall survival patient-reported outcome phase 1 clinical trial progression free survival protein expression relapse remission solid malignant neoplasm study design surgery T lymphocyte toxicity CAS REGISTRY NUMBERS carboplatin (41575-94-4) durvalumab (1428935-60-7) paclitaxel (33069-62-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619623353 DOI 10.1093/annonc/mdx372.063 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx372.063 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 11 TITLE A phase I study of durvalumab (D) in combination with olaparib (O) and cediranib (C) in recurrent women's cancers AUTHOR NAMES Zimmer A. Peer C. Cao L. Kohn E. Lipkowitz S. Annunziata C. Trepel J. Lee M.J. Mikkilineni L. Gatti-Mays M. Nunes A. Soltani S. Figg W.D. Houston N. Nichols E. Lee J.-M. AUTHOR ADDRESSES (Zimmer A.) Women's Malignancies Branch, National Cancer Institute National Institutes of Health, Bethesda, United States. (Peer C.; Cao L.; Kohn E.; Trepel J.; Lee M.J.; Mikkilineni L.; Gatti-Mays M.; Nunes A.; Soltani S.; Figg W.D.) Center for Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, United States. (Lipkowitz S.; Annunziata C.; Houston N.; Nichols E.; Lee J.-M.) Women's Malignancies Branch, National Institutes of Health, Bethesda, United States. CORRESPONDENCE ADDRESS A. Zimmer, Women's Malignancies Branch, National Cancer Institute National Institutes of Health, Bethesda, United States. SOURCE Annals of Oncology (2017) 28 Supplement 5 (v130). Date of Publication: 1 Sep 2017 CONFERENCE NAME 42nd ESMO Congress, ESMO 2017 CONFERENCE LOCATION Madrid, Spain CONFERENCE DATE 2017-09-08 to 2017-09-12 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Recent data showed a PARP inhibitor, O and a VEGFR1-3 inhibitor, C together are clinically superior to O alone in recurrent platinum-sensitive ovarian cancer (OvCa). We hypothesized reduced VEGF signaling by C and DNA damage by O may complement anti-tumor activity of immune checkpoint blockade, D. We previously reported the safety data and RP2D of D in combination with O or C. We now report RP2D and PK/PD data of the D+O+C therapy (NCT02484404). Methods: Eligible patients (pts) with PS 0-1 and good end organ function received D+O+C in a 3+3 design. An intermittent C schedule (C; 5 days on/2 days off) at 15 or 20 mg (dose level: 1, 2) was combined with D 1500 mg IV q28 days, and O tablets 300 mg BID. The DLT period was one 28d cycle. Safety was assessed by CTCAEv4.0 and response by RECISTv1.1. Plasma samples were collected for O and C PK analysis and for pro-inflammatory cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-6, IL-8 and TNF-a) pretreatment and on therapy (cycle 1 day 15 and cycle 3 day 1). Results: Nine women (median age 59yr [44-73], and median 3 prior therapies [2-6]) were treated. Of the 9 pts, 7 had OvCa, 1 endometrial (EnCa) and 1 triple negative breast Ca. Grade 3/4 AEs include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No pts experienced DLTs. One patient required dose reduction during cycle 5, for grade 3 anemia. Three PRs were observed in 2 OvCa and 1 EnCa (response rate of 33%, median 5months [4+-6+]), and 4 had SD (median 5 months [3+-10+]), yielding 78% disease control rate. There were no significant changes in O and C PK parameters caused by D and the co-administration of C or O. All cytokines plasma levels were not changed significantly by the treatment. PD-L1 expression by IHC and immune subsets by flow cytometry are under analysis. Conclusions: The RP2D for D+O+C (D 1500 mg q28d+O 300 mg tablets BID+C 20 mg 5 days on/2 days off) is tolerable and active in recurrent women's cancers. A phase II expansion study of D+O+C is to open in OvCa. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) cediranib durvalumab olaparib EMTREE DRUG INDEX TERMS calcium endogenous compound gamma interferon interleukin 10 interleukin 12 interleukin 2 interleukin 6 interleukin 8 programmed death 1 ligand 1 tumor necrosis factor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer recurrence ovary cancer EMTREE MEDICAL INDEX TERMS adult anemia antineoplastic activity breast clinical article clinical trial disease control DNA damage drug combination ECC-1 cell line endometrium female flow cytometry gene expression human human cell human tissue hypertension immunohistochemistry lymphocytopenia middle aged phase 1 clinical trial phase 2 clinical trial plasma protein blood level tablet VEGF signaling CAS REGISTRY NUMBERS calcium (7440-70-2, 14092-94-5) cediranib (288383-20-0, 857036-77-2) durvalumab (1428935-60-7) gamma interferon (82115-62-6) interleukin 12 (138415-13-1) interleukin 2 (85898-30-2) interleukin 8 (114308-91-7) olaparib (763113-22-0) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619623546 DOI 10.1093/annonc/mdx367.024 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx367.024 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 12 TITLE Vanucizumab (VAN) in combination with atezolizumab (ATEZO) for platinum-resistant recurrent ovarian cancer (PROC): Results from a single arm extension phase of the phase I study BP28179 AUTHOR NAMES Oaknin A. Vergote I. Ray-Coquard I. Leary A. Rodriguez Freixinos V. Concin N. Toussaint P. Massard C. Fariñas-Madrid L. Van Nieuwenhuysen E. Lahr A. Franjkovic I. Rossomanno S. Gerber P. Nayak T. Heil F. Boetsch C. Sahbi A. Longauer K. Krieter O. AUTHOR ADDRESSES (Oaknin A.; Rodriguez Freixinos V.; Fariñas-Madrid L.) Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (Vergote I.; Concin N.; Van Nieuwenhuysen E.) Department of Obstetrics and Gynaecology and Gynaecologic Oncology, University Hospital, Leuven, Belgium. (Ray-Coquard I.; Toussaint P.) Oncologie Médicale, Université Claude Bernard Lyon I, Lyon, France. (Leary A.; Massard C.) Gynecology Unit, Institut Gustave Roussy, Villejuif, France. (Lahr A.; Franjkovic I.; Heil F.; Krieter O.) Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany. (Rossomanno S.; Gerber P.; Nayak T.; Boetsch C.; Longauer K.) Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (Sahbi A.) Pharma Research and Early Development, Roche Innovation Center Welwyn, Welwyn, United Kingdom. CORRESPONDENCE ADDRESS A. Oaknin, Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. SOURCE Annals of Oncology (2017) 28 Supplement 5 (v335). Date of Publication: 1 Sep 2017 CONFERENCE NAME 42nd ESMO Congress, ESMO 2017 CONFERENCE LOCATION Madrid, Spain CONFERENCE DATE 2017-09-08 to 2017-09-12 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: VAN is a bi-specific human IgG1 antibody, simultaneously blocking two key angiogenic factors, Ang-2 and VEGF-A. VAN as a single agent showed an objective response rate (ORR) of 29% in bevacizumab- naïve PROC. The anti-PD-L1 agent, ATEZO demonstrated a 22% ORR in advanced OC. Preclinical data suggested additive antitumor activity of VAN when combined with anti-PD-L1. Hence, treatment with VAN plus ATEZO has the potential to reverse pro-angiogenic and immunesuppressive signals, thereby resulting in improved clinical benefit. Methods: Eligible patients (pts) had PROC measurable by RECIST 1.1. Pts with history of bowel obstruction, > 2 prior lines of systemic chemotherapy, or previous treatments with VEGF-A inhibitors or agents targeting Ang/Tie2 receptor axis were ineligible. Pts received VAN 2000 mg and ATEZO 840 mg, each IV Q2W, until disease progression or unacceptable toxicity. Primary efficacy endpoint was ORR as per RECIST 1.1, with tumor assessments every 8 weeks. Results: 17 pts with median age of 63 years (range 45-74) were treated. Serous histology was present in all pts, except one clear cell subtype. 4 pts (24%) achieved confirmed PR, 8 pts (47%) experienced SD and 4 (24%) had PD, while one patient was not evaluable. The achieved RECIST ORR of 24% remained unchanged when evaluated as per immune-related response criteria. 9/17 pts were evaluable for CA-125 per GCIG criteria; three and two achieved a response with and without normalization respectively. The current estimate of PFS rate @ 6 months is 65% (median follow-up: 162 days). The most common adverse events (AE) of any grade (G) were decreased appetite, diarrhea (41% each), asthenia and constipation (35% each). AEs≥ G3 included abdominal pain, LFT increase, asthenia, dyspnea, health deterioration, hypertension, GI obstruction, GI perforation (GIP), subileus, lymphedema, pleuritis and tonsillitis (6% each). One AE of GIP and asthenia each were fatal. Conclusions: Our data suggest that VAN plus ATEZO does not improve upon monotherapy with VAN or ATEZO in PROC. The safety profile of this combination is consistent with reports for the single agents in this setting. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) atezolizumab platinum vanucizumab EMTREE DRUG INDEX TERMS angiopoietin receptor CA 125 antigen endogenous compound programmed death 1 ligand 1 vasculotropin A EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer recurrence ovary cancer EMTREE MEDICAL INDEX TERMS abdominal pain adult adverse event antineoplastic activity asthenia chemotherapy clinical article clinical trial constipation decreased appetite deterioration diarrhea drug combination drug resistance drug therapy dyspnea female follow up histology human human tissue hypertension immune-related gene intestine obstruction lymphedema male middle aged monotherapy perforation phase 1 clinical trial pleurisy preclinical study response evaluation criteria in solid tumors tonsillitis toxicity CAS REGISTRY NUMBERS atezolizumab (1380723-44-3) platinum (7440-06-4) vanucizumab (1448221-05-3) vasculotropin A (489395-96-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619623586 DOI 10.1093/annonc/mdx372.012 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx372.012 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 13 TITLE Dose-finding combination study of niraparib and pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC) (TOPACIO/Keynote-162) AUTHOR NAMES Konstantinopoulos P.A. Sachdev J.C. Schwartzberg L. Matulonis U.A. Sun P. Wang J.Y. Guo W. Bobilev D. Aktan G. Karantza V. Dezube B. Vinayak S. AUTHOR ADDRESSES (Konstantinopoulos P.A.) Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, United States. (Sachdev J.C.) Oncology, Honor Health Research Institute, Scottsdale, United States. (Schwartzberg L.) Medical Oncology, West Clinic, Memphis, United States. (Matulonis U.A.) Gynecologic Oncology, Dana Farber Cancer Institute, Boston, United States. (Sun P.; Wang J.Y.; Bobilev D.; Dezube B.) Clinical Science, TESARO, Inc., Waltham, United States. (Guo W.) Biostatistics, TESARO, Inc., Waltham, United States. (Aktan G.) Clinical Research, Merck and Co., Inc., Kenilworth, United States. (Karantza V.) Oncology, Merck and Co., Inc., Kenilworth, United States. (Vinayak S.) Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States. CORRESPONDENCE ADDRESS P.A. Konstantinopoulos, Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, United States. SOURCE Annals of Oncology (2017) 28 Supplement 5 (v406-v407). Date of Publication: 1 Sep 2017 CONFERENCE NAME 42nd ESMO Congress, ESMO 2017 CONFERENCE LOCATION Madrid, Spain CONFERENCE DATE 2017-09-08 to 2017-09-12 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Platinum-resistant OC represents an unmet medical need with progression free survival (PFS) of 3.5 to 6 months. Niraparib, an oral PARP 1/2 inhibitor (PARPi), improved PFS in pts with recurrent OC following response to platinum (NEJM, 2016). Preclinical evidence suggests synergy between PARPis and PD-1 inhibitors in OC and TNBC. We report data from a phase 1 niraparib + pembrolizumab (pembro) combination study leading to recommended phase 2 dose (RP2D). Methods: Primary objectives were to assess dose limiting toxicities (DLTs) in a 6+6 dose escalation design and determine RP2D. Eligible pts had metastatic TNBC treated with ≤4 prior lines of chemotherapy OR platinum-resistant recurrent OC treated with ≤5 prior lines of chemotherapy having responded with CR or PR for >6months to 1st line platinum based chemotherapy. Results: The 14 pts (≥18 yrs) enrolled received pembro 200 mg IV on day 1 and niraparib 200 mg (dose level [DL] 1, n=7; 2 TNBC, 5 OC) or 300 mg (DL2, n=7; 3 TNBC, 4 OC) PO on days 1-21 of each 21-day cycle. In DL1, 1 pt had DLTs (neutropenia, anemia and thrombocytopenia) and discontinued niraparib but continued pembro. In DL2, 1 pt had DLT and 1 had DLT-equivalent (both thrombocytopenia); both resumed treatment with 200 mg niraparib and continued pembro. RP2D was determined as niraparib 200 mg PO daily + pembro 200 mg IV on day 1 of each 21-day cycle. Based on RECIST v1.1, 4/8 evaluable OC pts responded; the other 4 pts achieved SD (Table). 1/5 TNBC pts (BRCA wildtype) had SD for 10 cycles. BRCA & PD-L1 status will be presented. Conclusions: This study established a RP2D, and showed preliminary efficacy of niraparib and pembro combination for treatment of heavily pretreated TNBC or platinumresistant OC. No significant overlapping toxicity was noted. A phase 2 study is currently enrolling. Supporting translational work funded by SU2C. (Table Presented). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) niraparib pembrolizumab platinum EMTREE DRUG INDEX TERMS endogenous compound programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer recurrence dose calculation ovary carcinoma triple negative breast cancer EMTREE MEDICAL INDEX TERMS adult adverse drug reaction anemia cancer patient chemotherapy clinical article clinical trial drug combination drug resistance drug therapy female human male neutropenia phase 1 clinical trial phase 2 clinical trial response evaluation criteria in solid tumors side effect thrombocytopenia toxicity CAS REGISTRY NUMBERS niraparib (1038915-60-4) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619623123 DOI 10.1093/annonc/mdx376.009 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx376.009 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 14 TITLE Association between the development of autoimmune hypothyroidism and objective response to nivolumab: report of two cases AUTHOR NAMES Di Lucca G. Rossini C. Morena R. Banfi L. Pogliani C. Parati M.C. Sali L. Troisi A. Verusio C. AUTHOR ADDRESSES (Di Lucca G.) Struttura Complessa Di Oncologia Medica, ASST Vallo Olona - Ospedale Di Saronno, Saronno, Italy. (Rossini C.; Morena R.; Banfi L.; Pogliani C.; Parati M.C.; Verusio C.) Struttura Complessa Di Oncologia Medica, ASST Valle Olona - Ospedale Di Saronno, Saronno, Italy. (Sali L.; Troisi A.) Struttura Complessa Di Medicina Interna, ASST Valle Olona - Ospedale Di Saronno, Saronno, Italy. CORRESPONDENCE ADDRESS G. Di Lucca, Struttura Complessa Di Oncologia Medica, ASST Vallo Olona - Ospedale Di Saronno, Saronno, Italy. SOURCE Annals of Oncology (2017) 28 Supplement 6 (vi99). Date of Publication: 1 Oct 2017 CONFERENCE NAME 19th National Congress of Medical Oncology CONFERENCE LOCATION Rome, Italy CONFERENCE DATE 2017-10-27 to 2017-10-29 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT The use of checkpoint inhibitors has been rapidly growing, despite the relative lack of predictive factors. Their toxicity includes a spectrum of autoimmune disorders, thyroid dysfunctions being one of the commonest. Correlation between autoimmune thyroiditis and antitumor immunity has been well demonstrated in experimental models and the development of autoimmune hypothyroidism has been postulated to be predictive of objective tumor response in patients treated by high-dose IL-2. Immune-related thyroid dysfunctions have been reported in as many as 20% of cancer patients treated by checkpoint inhibitors, but until now no clear relationship between thyroid disorders and tumor regression has been described.We hereby describe two cases in which the appearance of autoimmune hypothyroidism heralded radiographic response to nivolumab. 1) A 75-year-old woman with metastatic renal cell carcinoma progressing on sunitinib with massive left pleural effusion and multiple lung metastases started i.v. nivolumab 3 mg/kg q2w. Three months later a CT scan showed complete resolution of pleural effusion and almost complete disappearance of lung metastases. Concurrently, measurement of serum TSH showed values > 75 mcIU/ml with FT4 0.3 ng/dl (normal range 0.8-1.7). Anti-TPO autoantibodies were > 1000 IU/ml (range 0-6). Treatment with levo-tiroxine ensued with progressive titration to assure normal thyroid function. Nivolumab was continued and the patient is in vgPR 12 months after beginning treatment. 2) A 69-year-old man with stage IIIB squamous cell lung cancer progressing after induction platinum-based chemotherapy and during mediastinal RT began i.v. nivolumab 3 mg/kg q2w. After a minor response at first evaluation, he presented with peripheral and periorbital edema, profound asthenia and somnolence. TSH serum levels were >75 mcIU/ml, FT4 was<0.3 ng/dl, anti-TPO antibodies were >1000 IU/ml and anti- TG were 130 IU/ml (range 0-6). Levo-tiroxine was immediately started with rapid clinical improvement. A subsequent CT scan showed PR. The patient is continuing nivolumab, thyroid function is balanced and clinical signs of toxicity have completely resolved. The parallel development of autoimmune thyroiditis and tumor response upon nivolumab suggests a shared mechanism of antigen recognition and deserves to be elucidated to identify possible predictive factors of anti-PD1 activity. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS autoantibody endogenous compound platinum sunitinib EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypothyroidism EMTREE MEDICAL INDEX TERMS aged antigen recognition asthenia autoimmune thyroiditis cancer patient cancer staging case report chemotherapy drug combination drug therapy female human human tissue immune-related gene kidney metastasis lung metastasis male mediastinum periorbital edema peripheral edema pleura effusion protein blood level somnolence squamous cell lung carcinoma thyroid function thyrotropin blood level titrimetry toxicity tumor regression x-ray computed tomography CAS REGISTRY NUMBERS nivolumab (946414-94-4) platinum (7440-06-4) sunitinib (341031-54-7, 557795-19-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619569113 DOI 10.1093/annonc/mdx436 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx436 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 15 TITLE Efficacy of pembrolizumab (MK-3475) in patients with adrenocortical carcinoma AUTHOR NAMES Habra M.A. Campbell M. Jimenez C. Karp D. Hong D. Subbiah V. Pant S. Painter J. Khan S. Bernatchez C. Stephen B. Alshawa A. Tapia C. Mendoza T. Colen R. Hess K. Meric-Bernstam F. Naing A. AUTHOR ADDRESSES (Habra M.A.; Campbell M.; Jimenez C.; Karp D.; Hong D.; Subbiah V.; Pant S.; Painter J.; Khan S.; Bernatchez C.; Stephen B.; Alshawa A.; Tapia C.; Mendoza T.; Colen R.; Hess K.; Meric-Bernstam F.; Naing A., anaing@mdanderson.org) MD Anderson Cancer Center, Houston, United States. CORRESPONDENCE ADDRESS A. Naing, MD Anderson Cancer Center, Houston, United States. Email: anaing@mdanderson.org SOURCE Journal for ImmunoTherapy of Cancer (2017) 5 Supplement 2. Date of Publication: 1 Nov 2017 CONFERENCE NAME 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer, SITC 2017 CONFERENCE LOCATION National Harbor, MD, United States CONFERENCE DATE 2017-11-08 to 2017-11-12 ISSN 2051-1426 BOOK PUBLISHER BioMed Central Ltd. ABSTRACT Background Adrenocortical carcinoma (ACC) is an orphan endocrine malignancy with poor prognosis and limited response to chemotherapy. ACC can express immune markers which could make it susceptible to immunotherapy. So far, there is no published clinical trial about using immunotherapy in ACC. Methods This is a phase II study of pembrolizumab in patients with rare tumors including a pre-specified ACC cohort (http://ClinicalTrials.- gov identifier, NCT02721732). Patients received pembrolizumab 200 mg intravenously once every 3 weeks. Response was assessed every 9 weeks using RECIST1.1. The primary end point was progression-free survival at 27 weeks (PFS27wk). Mandatory biopsies are taken at baseline, on cycle 1 day 15 -21, and at the time of progression. Results A total of 11 patients were enrolled and treated. At the time of analysis, patients received a median of 6 treatment cycles (range 2-17). A PFS of greater than 27 weeks was seen in 3/11 patients (27%). The first patient reached 37% tumor reduction (partial response) while the second patient had a response of 41% tumor reduction (partial response) and the third patient had stable disease. The remaining 8 patients had evidence of disease progression within 27 weeks of starting the study (median time 18 weeks, range 6-27 weeks). Progression was seen in most patients with hormonally active ACC (6/7) and only in 2/4 patients without evidence of hormonal excess at the time of their initial diagnosis. The safety profile of pembrolizumab was very favorable and none of these patients had severe grade 3 or grade 4 adverse effects. Conclusions Single agent pembrolizumab may be an effective option in subset of ACCs without hormonal overproduction while it is associated with high failure rate among patients with hormonally active ACCs. Expanding the study to hormonally silent ACCs is needed to verify the initial observation from limited number of patients treated in this study. Translational data will be presented at this meeting. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal cortex carcinoma EMTREE MEDICAL INDEX TERMS adult adverse event biopsy cancer survival clinical article clinical trial cohort analysis diagnosis drug therapy female gene overexpression human human tissue male pharmacokinetics phase 2 clinical trial progression free survival treatment failure CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619370606 DOI 10.1186/s40425-017-0288-4 FULL TEXT LINK http://dx.doi.org/10.1186/s40425-017-0288-4 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 16 TITLE Nivolumab and diabetes mellitus: Safe administration in a patient with pancreatic metastases from melanoma AUTHOR NAMES Gambale E. Tinari C. Quinzii A. Cortellini A. Carella C. De Tursi M. AUTHOR ADDRESSES (Gambale E., gambaleelisabetta@gmail.com; Quinzii A.; De Tursi M.) Department of Medical, Oral and Biotechnological Sciences, G. D'Annunzio University of Chieti-Pescara, Chieti, Italy. (Tinari C.) Unit of Endocrinology, Department of Medicine and Sciences of Aging, Ce.S.I.-Me.T., G.D' Annunzio University of Chieti-Pescara, Chieti, Italy. (Cortellini A.) Medical Oncology, San Salvatore Hospital, L'Aquila, Italy. (Cortellini A.) Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. (Carella C.) Oncology Unit, SS. Annunziata Hospital, Chieti, Italy. CORRESPONDENCE ADDRESS E. Gambale, Department of Medical, Oral and Biotechnological Sciences, G. D'Annunzio University of Chieti-Pescara, Chieti, Italy. Email: gambaleelisabetta@gmail.com SOURCE Journal of Translational Medicine (2017) 15 Supplement 1 (11). Date of Publication: 2017 CONFERENCE NAME 2nd Annual Immunotherapy Bridge and Melanoma Bridge 2016 CONFERENCE LOCATION Naples, Italy CONFERENCE DATE 2016-11-30 to 2016-12-03 ISSN 1479-5876 BOOK PUBLISHER BioMed Central Ltd. ABSTRACT Background: Anti-programmed cell death-1 (PD-1) antibodies can be a risk factor for insulin dependent diabetes mellitus as a side-effect, probably due to an inappropriate activation of T cells [1, 2, 3]. Very small number of cases have been reported and few data are available about patients treated with anti-PD-1 antibodies with of other risk factors for diabetes, included combined use with other immune modulators, pancreatic metastases and preexisting type 2 diabetes [4]. Here we report our recent experience of a patient underwent pancreatoduodenectomy for pancreatic metastases from melanoma and treated with Nivolumab. Case report: A 45-year-old man was admitted to our Oncology Unit in June 2016 with the diagnosis of metastatic melanoma. ECOG Performance Status was 0 and no comorbidities were reported. In May 2016 pathological lymph nodes in left inguinal region were removed surgically and the histological diagnosis was metastases from melanoma, BRAF mutated. In June 2016, he underwent pancreatoduodenectomy for metastases of melanoma in the head of the pancreas. On July 2016, he started Nivolumab administered at 3 mg/kg intravenously, every 2 weeks. Basal glycemia, islet autoantibodies, haemoglobin A1c and serum C-peptide levels were normal. The last haematological reports, performed on 16 August 2016, showed hyperglycemia (131 mg/dl-reference range:74-106), normal levels of serum C-peptide, absence of islet autoantibodies and elevated haemoglobin A1c level (42 mmol/mol- reference range: 20.0-38.0). At this moment, he continues Nivolumab and he is constantly monitored for his increased risk of diabetes. Discussion: Our research in the literature found only four reports (eight cases) of diabetes mellitus during treatment with anti- PD-1 antibodies and, among these, only a case of patient with pancreatic metastases, probably also due to the rarity of pancreatic metastases from melanoma [3,4,5]. All described reports develop acute severe hyperglycemia with ketoacidosis or low/undetectable C-peptide, with a rapid fall into insulin-dependence; the islet autoantibodies are often negative. Considering the rapid onset, severity and potential mortality of those situations, routine measurement of both haemoglobin A1c and blood glucose levels is necessary during administration of anti-PD-1 antibodies [3]. Our single-patient experience demonstrates that administration of Nivolumab is safe and well tolerated even in presence of risk factors for diabetes. However, further accumulation of cases, evidence and further studies are required to clarify the incidence of diabetes mellitus, the pathogenesis and the background factors and to identify biomarkers predictive of anti-PD-1 therapy-related diabetes, for the prevention and the timely diagnosis of this serious adverse event [3, 4]. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS autoantibody B Raf kinase biological marker C peptide endogenous compound hemoglobin A1c programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) diabetes mellitus metastatic melanoma pancreas metastasis EMTREE MEDICAL INDEX TERMS adult adverse event clinical article comorbidity diagnosis drug therapy gene mutation head histology human human tissue hyperglycemia incidence inguinal region insulin dependence ketoacidosis lymph node male middle aged mortality oncology pancreas islet pancreaticoduodenectomy risk factor surgery CAS REGISTRY NUMBERS C peptide (59112-80-0) hemoglobin A1c (62572-11-6) nivolumab (946414-94-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619389880 DOI 10.1186/s12967-016-1095-2 FULL TEXT LINK http://dx.doi.org/10.1186/s12967-016-1095-2 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 17 TITLE Incidence of thyroid test function abnormalities in patients receiving immune-checkpoint inhibitors for cancer treatment AUTHOR NAMES Patel N. Oury A. Daniels G. Bazhenova L. Patel S. AUTHOR ADDRESSES (Patel N., nip011@ucsd.edu; Oury A.; Daniels G.; Bazhenova L.; Patel S.) University of California San Diego, San Diego, United States. CORRESPONDENCE ADDRESS N. Patel, University of California San Diego, San Diego, United States. Email: nip011@ucsd.edu SOURCE Journal for ImmunoTherapy of Cancer (2017) 5 Supplement 2. Date of Publication: 1 Nov 2017 CONFERENCE NAME 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer, SITC 2017 CONFERENCE LOCATION National Harbor, MD, United States CONFERENCE DATE 2017-11-08 to 2017-11-12 ISSN 2051-1426 BOOK PUBLISHER BioMed Central Ltd. ABSTRACT Background With the advent of immune-checkpoint inhibitor (ICI) therapy (anti- CTLA-4, anti-PD-1), immune related adverse events (irAE) such as thyroid function test abnormalities (TFTA) are common with a reported incidence range of 2-15% depending upon the ICI utilized [1,2]. The aim of this study was to describe the incidence of TFTAs retrospectively in patients who received ICI therapy. Methods A total of 285 patients were reviewed (178 male, 107 female; ages 16-94) of which 218 had no baseline TFTA, 61 had baseline TFTAs, and 6 had history of thyroidectomy and were excluded. Patients received at least one dose of ipilimumab and/or nivolumab or pembrolizumab. Post-ICI therapy TFTA was classified according to definitions of thyroid abnormalities when possible [3]. Results A total of 35% (76/218) patients had new onset TFTAs on ICI therapy. Of note, 70.5% (43/61) had baseline TFTA that were exacerbated by ICI therapy. Median time to new onset or exacerbated baseline TFTA were 46 & 33 days respectively. Of note, 65% (20/31) of patients on both ipilimumab and nivolumab had new onset TFTA, compared to 31.3% (15/48) with ipilimumab, 31.5% (28/89) nivolumab, 26% (13/50) pembrolizumab (Table 1). Conclusions The incidence of TFTAs with ICI therapy was higher than previously reported. Patients with baseline TFTA and/or receiving ipilimumab and nivolumab combination therapy had a higher incidence of TFTA than one agent ICI therapy. In conclusion, we recommend more frequent evaluation of TFT in the first two months, especially in those with baseline TFTA. EMTREE DRUG INDEX TERMS ipilimumab nivolumab pembrolizumab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer therapy congenital malformation incidence EMTREE MEDICAL INDEX TERMS adolescent adult aged cancer surgery clinical trial drug combination drug therapy female human major clinical study male patient history of thyroidectomy retrospective study thyroid disease thyroid function test CAS REGISTRY NUMBERS ipilimumab (477202-00-9) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619371287 DOI 10.1186/s40425-017-0288-4 FULL TEXT LINK http://dx.doi.org/10.1186/s40425-017-0288-4 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 18 TITLE Immune-related endocrinopathies during immune checkpoint blockade AUTHOR NAMES Shimatsu A. AUTHOR ADDRESSES (Shimatsu A.) Clinical Research Institute, National Hospitral Organization, Kyoto Medical Center, Japan. CORRESPONDENCE ADDRESS A. Shimatsu, Clinical Research Institute, National Hospitral Organization, Kyoto Medical Center, Japan. SOURCE Annals of Oncology (2017) 28 Supplement 9 (ix29). Date of Publication: 1 Oct 2017 CONFERENCE NAME 15th Annual Meeting of Japanese Society of Medical Oncology, JSMO 2017 CONFERENCE LOCATION Kobe, Japan CONFERENCE DATE 2017-07-27 to 2017-07-29 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT The cancer immunotherapy is associated with serious immune-related adverse effects (irAEs). Although endocrinopathies are not among the most common irAEs, they can be severe and must be carefully monitored for during treatment. The two main endocrinopathies observed with checkpoint blockade treatments include thyroid dysfunction and hypophysitis. Primary thyroid dysfunction was reported in about 10% of patients treated with PD-1 antibodies and with CTLA-4 antibodies. Primary hypothyroidismand transient thyrotoxicosis were reported. Monitoring patients for signs of hypothyroidism, such as fatigue, weight gain and cold intolerance, is important. In addition to baseline thyroid function tests, subsequent tests should be measured during treatment. Primary hypothyroidism should be treated using levothyroxine hormone replacement therapy. The patients with mild symptoms of thyrotoxicosis from thyroiditis can be observed and monitored for symptom progression, as well as for the development of permanent hypothyroidism. The incidence of hypophysitis related to CTLA-4 antibody therapy has been reported in 9.1% of patients; mostly secondary adrenal insufficinecy, secondary hypothyroidism and secondary hypogonadism. The time for the onset of symptoms can range from 6 weeks to 12 weeks after treatment initiation. Headache, fatigue and muscle weakness seem to be the most common symptoms and nausea, anorexia, weight loss, alterations in mental status, arthralgia and hyponatremia have been reported. Adrenal crisis require immediate treatment with corticosteroids and fluid. Mild-to-modarate diffuse enlargement of the pituitary gland was seen on sellarMRI. In cases treated with PD-1 antibodies, pituitary enlargement was minimal. Management should be based on clinical presentation and evaluation of pituitary hormone levels. Levothyroxine can be used to treat secondary hypothyroidism, but glucocorticoid deficiency should be first treated to avoid any potential adrenal crisis. EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 antibody endogenous compound glucocorticoid hypophysis hormone levothyroxine programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency immune-related gene EMTREE MEDICAL INDEX TERMS adult anorexia arthralgia body weight gain body weight loss clinical evaluation cold stress disease course drug therapy female gene expression headache hormone substitution human hypogonadotropic hypogonadism hyponatremia hypophysitis hypothyroidism incidence liquid male mental health monitoring muscle weakness nausea thyroid function test thyroiditis thyrotoxicosis CAS REGISTRY NUMBERS hypophysis hormone (85883-81-4) levothyroxine (51-48-9) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619368393 DOI 10.1093/annonc/mdx564 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdx564 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 19 TITLE STING agonist treatment increases response to chemotherapy and immune checkpoint blockade therapy in a syngeneic murine model of high-grade serous ovarian cancer AUTHOR NAMES Ghaffari A. Peterson N. Khalaj K. Robinson A. Francis J.-A. Koti M. AUTHOR ADDRESSES (Ghaffari A.; Peterson N.; Khalaj K.; Koti M., kotim@queensu.ca) Queen's University, Kingston, Canada. (Robinson A.; Francis J.-A.) Kingston Health Sciences Center, Kingston, Canada. CORRESPONDENCE ADDRESS M. Koti, Queen's University, Kingston, Canada. Email: kotim@queensu.ca SOURCE Journal for ImmunoTherapy of Cancer (2017) 5 Supplement 2. Date of Publication: 1 Nov 2017 CONFERENCE NAME 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer, SITC 2017 CONFERENCE LOCATION National Harbor, MD, United States CONFERENCE DATE 2017-11-08 to 2017-11-12 ISSN 2051-1426 BOOK PUBLISHER BioMed Central Ltd. ABSTRACT Background Background: High Grade Serous Carcinoma of the ovary is mostly diagnosed at late stages and primarily treated with surgery followed by platinum/taxane chemotherapy. Unfortunately, majority of the patients exhibit resistance to chemotherapy and ultimately succumb to the disease. We previously reported that tumours from patients with early recurrence show an immunosuppressed pre-existing tumour immune microenvironment with decreased expression of genes involved in Type I Interferon (IFN1) and T helper type 1 response [1, 2, 3]. We thus hypothesized that response to chemotherapy and overall survival of HGSC patients can be improved by stimulating the IFN1 response in the TME post chemotherapy. Methods In this pre-clinical study we tested the efficacy of a novel “Stimulator of Interferon Genes” agonist in immunocompetent mice implanted with ID8-TRP53-/- mouse ovarian cancer cells. Post treatment tumour immune cell profiles were measured using a combination of flow cytometry and CyTOF based profiling. Tumour immune transcriptomic alterations were measured using the NanoString mouse pan cancer immune profiling panel. Log-rank test based survival analysis was performed to determine significant differences in overall survival post treatment. Results Flow cytometry and NanoString based analysis of tumours collected at endpoint showed higher intra-tumoural PD-1+ and CD69+CD62L-, CD8+T cells, increased expression of IFN response, antigen presentation and MHCII, genes, respectively, in tumours from STING agonist treated mice compared to those from vehicle treated mice. In addition to significantly decreased ascites accumulation and decreased tumour burden, survival of mice treated with a combination of Carboplatin + STING agonist + anti-PD-1 therapy was significantly longer compared to Carboplatin + STING agonist, Carboplatin only, STING only and vehicle treated mice. Conclusions Findings from this study are foundational to future clinical trials aimed at combinatorial immunomodulatory therapies to improve chemotherapy response and overall survival of HGSC patients. EMTREE DRUG INDEX TERMS carboplatin endogenous compound interferon L selectin platinum programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) agonist chemotherapy murine model ovary cancer EMTREE MEDICAL INDEX TERMS adult animal cell animal experiment animal model antigen presentation ascites cancer size cancer survival CD8+ T lymphocyte controlled study drug combination drug therapy female flow cytometry immunocompetent cell log rank test male mouse nonhuman overall survival preclinical study survival analysis CAS REGISTRY NUMBERS carboplatin (41575-94-4) L selectin (126880-86-2) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619370677 DOI 10.1186/s40425-017-0288-4 FULL TEXT LINK http://dx.doi.org/10.1186/s40425-017-0288-4 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 20 TITLE Immune checkpoint markers in lung large cell neuroendocrine carcinomas (L-LCNEC) AUTHOR NAMES Abdel Karim N. Sendilnathan A. Eldessouki I. Orr-Asman M. Xie C. Wang J. Elnakat H. AUTHOR ADDRESSES (Abdel Karim N.; Sendilnathan A.; Eldessouki I.; Orr-Asman M.; Elnakat H.) Hematology/Oncology, University of Cincinnati, Cincinnati, United States. (Xie C.) Enviromental Health Department, University of Cincinnati, Cincinnati, United States. (Wang J.) Pathology, University of Cincinnati, Cincinnati, United States. CORRESPONDENCE ADDRESS N. Abdel Karim, Hematology/Oncology, University of Cincinnati, Cincinnati, United States. SOURCE Journal of Thoracic Oncology (2017) 12:11 Supplement 1 (S1583-S1584). Date of Publication: 1 Nov 2017 CONFERENCE NAME 2017 Chicago Multidisciplinary Symposium in Thoracic Oncology CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-09-14 to 2017-09-17 ISSN 1556-1380 BOOK PUBLISHER Elsevier Inc. ABSTRACT Background: L-LCNEC is a rare, highly aggressive tumor accounting for 2-3% of all lung cancers. Traditionally classified under non-small cell lung cancer (NSCLC), it is currently grouped with lung neuroendocrine tumors and classified next to small cell lung cancer (SCLC) with respect to biologic aggressiveness. Despite treatment with front line systemic chemotherapy regimens for SCLC or NSCLC, prognosis remains poor. Hence, the need to identify molecular markers to help determine the best therapies. Given the efficacy and recent success with immunotherapy in a number of tumor types, we set out to determine the level of a number of immune markers in addition to other proteins which could potentially further help in classification of L-LCNEC. Methods: Immunohistochemistry analyses were performed on an LCNEC tissue microarray (TMA) from US Biomax containing 24 cases (3 cores/patient) of varying stages ranging from I-IIIb using antibodies to determine the levels of Ki67, p53, PD-1 and PDL-1. All stained slides were scored by a pathologist. Results: In the 24 cases tested, there was no correlation between the percent of Ki67, a marker of tumor proliferation and stage of the disease. Moreover, p53 and most likely the mutant form of the protein was detected in 7/24 cases with 5/7 having greater than 70% expression. With regards to PD-L1, tumoral expression was present in 5/24 (21%) cases although 2 of them only had 1% or less tumoral staining in only 1/3 cores on the TMA. PD-L1 positive stromal lymphocytes occurred in 10/24 (42%) cases with overall staining of 5% of the cells or less except in one case. PD-1-positive stromal lymphocytes were present in 10/24 (42%) cases with 5 cases expressing 2% or less positive cells. Conclusion: There was no apparent correlation between any of the markers tested and disease stage. Additionally, presence of p53 staining could potentially serve as a marker to guide the choice of a SCLC over NSCLC therapeutic regimen for patients. Of note, PD-L1 has been reported to have a tumoral score of 50% or more in 20% of the NSCLC patients compared to a score of 50% inw4% of the cases tested here. We are further validating these preliminary findings in a larger number of L-LCNEC samples. Overall, characterization of the immune infiltration and checkpoint marker expression will help optimize the design of clinical trials for L-LCNEC using immune check point inhibitors. EMTREE DRUG INDEX TERMS antibody endogenous compound Ki 67 antigen programmed death 1 ligand 1 programmed death 1 receptor protein p53 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) large cell neuroendocrine carcinoma non small cell lung cancer EMTREE MEDICAL INDEX TERMS adult cancer patient cancer staging classification clinical article clinical trial controlled clinical trial controlled study female gene expression gene mutation human human cell human tissue immunohistochemistry immunotherapy lymphocyte male pathologist tissue microarray tumor growth LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619317669 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 21 TITLE Ipilimumab induced auto-immune hypophysitis AUTHOR NAMES Mian N. Rukmangadachar L. Choucair A. AUTHOR ADDRESSES (Mian N.; Rukmangadachar L.; Choucair A.) Springfield, United States. CORRESPONDENCE ADDRESS N. Mian, SOURCE Annals of Neurology (2017) 82 Supplement 21 (S29). Date of Publication: 1 Oct 2017 CONFERENCE NAME 142nd Annual Meeting of the American Neurological Association, ANA 2017 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2017-10-15 to 2017-10-17 ISSN 1531-8249 BOOK PUBLISHER John Wiley and Sons Inc. ABSTRACT Objective: We describe a case of Ipilimumab induced autoimmune hypophysitis. With the more common use of these drugs early recognition and prompt treatment of this rare side-effect is important to prevent morbidity and mortality. Background: A new era in the treatment of cancers is in the form of immunotherapy. One class of these drugs are Immune checkpoint inhibitors (anti-CTLA4, and anti-PD4), that are approved for the treatment of metastatic melanoma, non-small cell lung cancers, and renal cell carcinoma. Ipilumamab is an anti-CTLA4 monoclonal antibody that enhance anti-tumor immunity by targeting the T-cell inhibitory receptors. Adverse events might occur through immunologic activation and may involve every organ system. Neurological adverse events although rare, require prompt recognition and treatment to avoid substantial morbidity. Description: A 72 year old male with melanoma of the left abdominal wall with metastasis to the left inguinal lymph node, was admitted to the hospital with a four-day history of fatigue, generalized weakness, and confusion. The patient had received three treatments of immunotherapy with Ipilimumab for metastatic melanoma. After his third dose 2 weeks back, the patient reported malaise, poor appetite, vomiting, headache and diffuse erythematous papules from head to toe. At admission, he was alert, followed simple commands, however scored 10/30 on MMSE for missing points on all domains of the test, and otherwise a non-focal exam. His labs revealed hypoglycemia (blood glucose 60), and hyponatremia (129). Further endocrine testing was performed after he required repetitive administration of glucose to keep his blood glucose normal, that revealed low cortisol, ACTH and TSH suggesting pan hypopituitarism. MRI brain revealed abnormally enhancing and swollen pituitary in addition to a swollen pituitary stalk. CSF specimen revealed 26 WBC with lymphocytic predominance, 61 protein, normal glucose, and negative for an infectious source. The patient was treated with methylprednisolone 1gm IV daily for 5 days, and maintained on tapering steroid and thyroxine supplements. His mentation improved with steroids and he was back to his baseline in a week. Conclusion: Ipilumamab induced hypophysitis is a rare but significant neurological adverse event of immune checkpoint inhibitors, whose early recognition and treatment with steroids is important to prevent significant morbidity and mortality. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticotropin cytotoxic T lymphocyte antigen 4 endogenous compound glucose hydrocortisone thyrotropin thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune hypophysitis EMTREE MEDICAL INDEX TERMS abdominal wall adverse drug reaction aged appetite asthenia case report drug combination drug therapy fatigue glucose blood level headache human human cell hypoglycemia hyponatremia hypopituitarism immunotherapy inguinal lymph node malaise male metastatic melanoma Mini Mental State Examination morbidity mortality neurological complication non small cell lung cancer nuclear magnetic resonance imaging papule pituitary stalk prevention renal cell carcinoma side effect T lymphocyte thinking toe tumor immunity vomiting CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) glucose (50-99-7, 84778-64-3) hydrocortisone (50-23-7) ipilimumab (477202-00-9) thyrotropin (9002-71-5) thyroxine (7488-70-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L619084150 DOI 10.1002/ana.25024 FULL TEXT LINK http://dx.doi.org/10.1002/ana.25024 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 22 TITLE FDG-PET findings provide insights into thyroid-related side-effects in patients with advanced non-small cell lung cancer (NSCLC) treated with the immune checkpoint inhibitor Nivolumab AUTHOR NAMES Calamia I. Albertelli M. Nazzari E. Bauckneht M. Rossi G. Rijavec E. Genova C. Barletta G. Biello F. Dal Bello G. Piva R. Giusti M. Sambuceti G. Bagnasco M. Ferone D. Grossi F. Morbelli S. AUTHOR ADDRESSES (Calamia I.; Albertelli M.; Nazzari E.; Bauckneht M.; Rossi G.; Rijavec E.; Genova C.; Barletta G.; Biello F.; Dal Bello G.; Piva R.; Giusti M.; Sambuceti G.; Bagnasco M.; Ferone D.; Grossi F.; Morbelli S.) IRCCS AUO San Martino IST, Genova, Italy. CORRESPONDENCE ADDRESS I. Calamia, IRCCS AUO San Martino IST, Genova, Italy. SOURCE European Journal of Nuclear Medicine and Molecular Imaging (2017) 44:2 Supplement 1 (S673-S674). Date of Publication: 2017 CONFERENCE NAME 30th Annual Congress of the European Association of Nuclear Medicine, EANM 2017 CONFERENCE LOCATION Vienna, Austria CONFERENCE DATE 2017-10-21 to 2017-10-25 ISSN 1619-7089 BOOK PUBLISHER Springer Berlin Heidelberg ABSTRACT Background: Immune checkpoint blockade is associated with several endocrine-related adverse events including thyroid dysfunction that, however, still needs to be fully characterized. As several studies documented increased FDG uptake in thyroid gland in patients with thyroid autoimmunity, FDG-PET/CT images might further disclose the nature of thyroid disease onset after immunotherapy. In the present study, we aimed to evaluate the metabolic correlates of thyroid-related side-effects in NSCLC patients during therapy with Nivolumab (PD-1 receptor monoclonal antibody). Methods: 74 patients with advanced NSCLC underwent Nivolumab administration (4 mg/Kg every 14 days) within a single-institutional translational trial encompassing FDG-PET/CT every 4 cycles. 55/74 patients were evaluable for metabolic response assessment. Blood samples were collected at baseline and every cycle in order to monitor thyroid function and autoimmunity. Thyroid FDG uptake was semiquantitatively estimated by means of average SUV value (SUVmean). Presence/absence of focal uptake was also recorded. Finally, intensity of thyroid uptake was score-based assessed according to Deauville scale (DS). Results: At baseline, 6 patients showed impaired thyroid function (5 showed low and 1 increased TSH). During treatment, 4 patients developed transient thyrotoxicosis evolving to hypothyroidism in 3 cases. These patients showed increased autoantibodies, mainly anti-tireoglobulin (AbTg) and TSH after 6 months from therapy initiation. On the other hand, 8 patients developed hypothyroidism, with negative thyroid autoimmunity. No significant raise in SUVmean was highlighted (1.6±0.2 at baseline vs 1.9±0.3 after 6-8 months of therapy). Focal FDG thyroid uptake was recorded in one patient at baseline, while it appeared in two patients during therapy, corresponding to thyroid nodules in the absence suspected ultrasound features, thyroid dysfunctions or autoantibodies abnormalities. In the subgroup of 12 patients with thyroid-related side effects, changes in DS during treatment reflected better than SUVmean the alterations of thyroid function and autoimmunity. However, in 10/12 patients DS unexpectedly decreased during treatment. Moreover, in patients with hypothyroidism as well as and in a substantial percentage of the whole group of patients, DS score 1 more frequently occurred after treatment with respect to baseline, further testifying a reduction in thyroid FDG-avidity related to Nivolumab administration. Conclusion: Thyroid function abnormalities confirm to be the main endocrine adverse event related to Nivolumab. Hypothyroidism seems to be the most frequent of these effects. Autoantibodies type (mainly AbTg), the decrease in DS and their time-trend, support the hypothesis of a non-autoimmune pathophysiology underlying a substantial part of immunotherapy-related thyroid toxicity. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS autoantibody endogenous compound programmed death 1 receptor thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) non small cell lung cancer EMTREE MEDICAL INDEX TERMS adult adverse drug reaction autoimmunity blood cancer patient clinical trial congenital malformation controlled clinical trial controlled study drug therapy endocrine system female human hypothyroidism immunotherapy major clinical study male metabolism positron emission tomography-computed tomography side effect thyroid function thyroid nodule thyrotoxicosis toxicity ultrasound CAS REGISTRY NUMBERS nivolumab (946414-94-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618910162 DOI 10.1007/s00259-017-3822-1 FULL TEXT LINK http://dx.doi.org/10.1007/s00259-017-3822-1 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 23 TITLE Checkpoint inhibitor induced thyroid immune related adverse events: Two distinct clinical patterns AUTHOR NAMES Olsson-Brown A. Lord R. Sacco J. Upton J. Coles M. Pirmohamed M. AUTHOR ADDRESSES (Olsson-Brown A.; Sacco J.; Pirmohamed M.) University F Liverpool, Liverpool, United Kingdom. (Lord R.; Sacco J.; Upton J.) Clatterbridge Cancer Centre, Wirral, United Kingdom. (Coles M.) University of York, York, United Kingdom. CORRESPONDENCE ADDRESS A. Olsson-Brown, University F Liverpool, Liverpool, United Kingdom. SOURCE Drug Safety (2017) 40:10 (1034). Date of Publication: 1 Oct 2017 CONFERENCE NAME 17th ISoP Annual Meeting "Pharmacovigilance in the 21st Century" CONFERENCE LOCATION Liverpool, United Kingdom CONFERENCE DATE 2017-10-15 to 2017-10-18 ISSN 1179-1942 BOOK PUBLISHER Springer International Publishing ABSTRACT Background: Immune checkpoint inhibitors (CPI) are used in the main-stream treatment of a rapidly increasing number of malignancies. CPIs have novel toxicities compared to those recognised within oncology. These toxicities are immune related adverse events (irAEs) and clinically mimic autoimmune disease. One such irAE is thyroid dysfunction which, whilst rarely seen with the CTLA-4 inhibitor ipilimumab, has an incidence of 6-11% PD-1 inhibitors [1,2,3]. Thyroid irAEs have a significant clinical impact with permeant impairment, generally requiring long-term replacement; notable clinical, often multidisciplinary, input to stabilise endocrine function and frequently delays in oncological therapy [4]. Aims/Objectives: This study evaluated the clinical distribution of thyroid irAEs to determine hallmarks patterns specific to CPI thyroiditis Methods; A retrospective review of all patients treated with PD-1 CPI for metastatic melanoma treated at the Clatterbridge Cancer Centre over a 16-month period was undertaken identifying patients with thyroid irAEs. The clinical course and emerging clinical patterns of toxicity were evaluated to determine the presence of specific clinical trajectories within the patient cohort. Results: Between February 2016 and May 2017 89 patients with meta-static melanoma were treated with monotherapy PD-1 CPI, 12 (13.5%) of whom developed thyroid dysfunction. There were two distinct patterns identified: a hyperthyroid phase followed by a hypothyroid phase and de novo hypothyroidism. No additional patterns were identified. The majority of patients (66%) illustrated a hyper/hypo pattern where a period of hyperthyroidism was identified with peak T4 38.94 (23.1-52.0) and trough TSH\0.1. This pattern occurred following cycle 3 (range 2-8) of treatment. A subsequent decline in T4 followed within 6-21 days before hypothyroidism was identified in 8.5 weeks (range 3-10 weeks) from irAE commencement. Thirty-three percent of patients displayed de novo hypothyroidism. All patients were female and the irAE occurred after cycle 4 (range 2-6). The trough T4 was 4.15 (1-5.6) and the peak TSH 68.54 (51.26-79.35). All patients displayed minor symptoms inadequate to be considered clinical thyroid dysfunction. Steroids provided little benefit and the only pharmaceutical therapy required was levothyroxine. Symptomatic management for hyperthyroidism was not required by any patient within this series. All patients had permanent dysfunction requiring replacement. All continued with immunotherapy treatment but there were significant treatment hiatuses for toxicity, the longest of which was 5 months. Conclusions: This retrospective review has characterised the manifestation of thyroid irAE following CPI monotherapy which informs understanding and clinical management in terms particularly in terms of pattern, phase duration and pharmacological management. EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 endogenous compound ipilimumab levothyroxine programmed death 1 receptor steroid thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adverse event immune-related gene EMTREE MEDICAL INDEX TERMS adult cancer center cohort analysis drug therapy endocrine function female human hyperthyroidism hypothyroidism immunotherapy incidence major clinical study metastatic melanoma monotherapy retrospective study thyroiditis toxicity CAS REGISTRY NUMBERS ipilimumab (477202-00-9) levothyroxine (51-48-9) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618778713 DOI 10.1007/s40264-017-0580-8 FULL TEXT LINK http://dx.doi.org/10.1007/s40264-017-0580-8 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 24 TITLE Cancer testis antigens (CTA): The missing link in the pathogenesis of pregnancy- and immune checkpoint inhibitor-associated hypophysitis? AUTHOR NAMES Bose V. Gutenberg A. AUTHOR ADDRESSES (Bose V.; Gutenberg A.) Universitätsmedizin Mainz, Neurochirurgie, Mainz, Germany. CORRESPONDENCE ADDRESS V. Bose, Universitätsmedizin Mainz, Neurochirurgie, Mainz, Germany. SOURCE JDDG - Journal of the German Society of Dermatology (2017) 15 Supplement 3 (71-72). Date of Publication: 1 Aug 2017 CONFERENCE NAME 27. Deutschen Hautkrebskongresses, ADO 2017 CONFERENCE LOCATION Mainz, Germany CONFERENCE DATE 2017-09-21 to 2017-09-23 ISSN 1610-0387 BOOK PUBLISHER Wiley-VCH Verlag ABSTRACT Objective : Autoimmune lymphocytic hypophyistis is a rare disease that mostly affects women during or shortly after pregnancy and its autoantigens still await identification. In recent years, the use of immune checkpoint inhibitors in melanoma patients led to a steep rise in the incidence of hypophysitis as one of the major endocrine adverse events. Melanoma-associated antigens (MAGE) or so called cancer/testis-antigens (CTAs) are physiologically expressed in placenta as well as spermatogonia, and can be detected in different cancer types, e.g. melanoma and seminoma. Materials ans Methods : Immunohistochemical expression of 5 CTAs commonly expressed in melanoma and placenta (MAGE-A1, -A3,- A4, -C2, GAGE) were analysed in paraffin-embedded normal pituitary specimen from autopsy (n = 3) as well as in specimen from lymphocytic (n = 13) or granulomatous (n = 2) hypophysitis. Melanoma, seminoma and placenta served as positive controls. Results : We for the first time describe cytoplasmatic expression of MAGE-A1, -A3, -C2 and GAGE in normal acini cells of the adenohypophysis as well as the pituicytes of the posterior pituitary. Whereas pituitaries were negative for MAGE-A4. All hypophysitis specimen showed a markedly reduction or even a complete loss of CTA expressing acini cells. Giant cells of granulomatous hypophysitis revealed CTA expression in included (phagocytesed) cell debris. Conclusion : We for the first time describe the expression of CTAs in the endocrine and neurosecretory cells in normal pituitaries. The marked reduction of or even the loss of CTA expressing pituitary acini cells may reflect a selective destruction of these CTA expressing cells in autoimmune hypophysitis. CTAs therefore might be the pathogenetic autoimmune targets that bring together pregnancy-associated autoimmune to checkpoint inhibitor associated hypophysitis. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) cancer testis antigen EMTREE DRUG INDEX TERMS endogenous compound melanoma antigen 1 melanoma antigen 4 paraffin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune hypophysitis pregnancy EMTREE MEDICAL INDEX TERMS adenohypophysis autopsy clinical article controlled study destruction female gene expression giant cell granulomatosis human human cell human tissue immunohistochemistry lymphocyte male melanoma neurosecretory cell pituicyte placenta seminoma LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618667324 DOI 10.1111/ddg.13300 FULL TEXT LINK http://dx.doi.org/10.1111/ddg.13300 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 25 TITLE Immune checkpoint targeting to improve immunotherapy in neuroblastoma AUTHOR NAMES Ortiz-Ruiz M.L. AUTHOR ADDRESSES (Ortiz-Ruiz M.L.) H. Lee Moffitt Cancer Ctr., Res. Inst., Tampa, United States. CORRESPONDENCE ADDRESS M.L. Ortiz-Ruiz, H. Lee Moffitt Cancer Ctr., Res. Inst., Tampa, United States. SOURCE Cancer Research (2017) 77:13 Supplement 1. Date of Publication: 1 Jul 2017 CONFERENCE NAME American Association for Cancer Research Annual Meeting 2017 CONFERENCE LOCATION Washington, DC, United States CONFERENCE DATE 2017-04-01 to 2017-04-05 ISSN 1538-7445 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Neuroblastoma (NB) is the most common extracranial solid tumor in children. Current treatments accounts only for at the most 40% of survival rate in high-risk NB patients. Hence, there is a need to develop new strategies that disrupt immunosuppressive signals in the tumor microenvironment in order to achieve robust anti-tumor immune responses. Co-inhibitory signals through receptors such as PD-1 can lead to the inactivation of T cells. On the other hand, co-stimulatory signals through receptors such as 41BB can enhance T cell activity against tumors. These receptors can serve as tools to develop strategies to optimize and enhance T cell anti-tumor functions. In this study, we used 9464D NB tumor mouse model to evaluate antibody treatment as a possible immunotherapy strategy. We further examine the infiltration and function of T cells after targeting checkpoints in 9464D NB tumor bearing mice. Blockade of various receptors in mice bearing 9464D tumor showed that anti-PD1 and anti-41BB delayed tumor growth. Combination therapy with anti-PD1 and anti-41BB antibodies significantly delayed tumor growth compared to single antibody treatment. This combination therapy led to a higher infiltration of CD8+ cells within the tumor. Splenocytes from 9464D tumor bearing mice treated with anti-PD1 and anti-41BB are tumor specific. In conclusion, our findings intend to design the best complement therapy to improve survival of patients with advanced NB. Our data demonstrates that tumor reactive T cells in NB tumors may express different checkpoint receptors including PD1 and 41BB. 9464D tumor bearing mice that received a combination of anti-PD1 and anti-41BB antibodies have smaller tumor size compared to single antibody therapy. Future direction includes examine T cells activation after combination therapy of BMT and immunecheckpoint targeting. Also we want to test adoptive transfer of T cells in tumor bearing mice after BMT. Further we want to measure the infiltration of other immune cells, such as myeloid cells and Tregs, in the tumor environment and possible target immune suppressive populations to see the effects in tumor growth. EMTREE DRUG INDEX TERMS endogenous compound programmed death 1 receptor single chain fragment variable antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adoptive transfer neuroblastoma EMTREE MEDICAL INDEX TERMS animal cell animal experiment bone marrow cell cancer model cancer size cancer survival cell activity controlled study drug combination drug therapy immunocompetent cell mouse mouse model nonhuman overall survival regulatory T lymphocyte spleen cell tumor growth CAS REGISTRY NUMBERS single chain fragment variable antibody (334577-34-3, 334577-38-7) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618664390 DOI 10.1158/1538-7445.AM2017-689 FULL TEXT LINK http://dx.doi.org/10.1158/1538-7445.AM2017-689 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 26 TITLE Hypophysitis secondary to the checkpoint inhibitor Pembrolizumab-a rare condition, a new cause-A case report AUTHOR NAMES Anderson C. McKenna S. Santos A. Westrup J. Kelleher F. Griffin M. AUTHOR ADDRESSES (Anderson C.; Griffin M.) UCD School of Medicine and Medical Science, Ireland. (McKenna S.) Department of Diabetes, Beacon Hospital, Ireland. (Santos A.; Westrup J.) Department of Medical Oncology, Beacon Hospital, Ireland. (Kelleher F.) Department of Medical Oncology, St James' University Hospital, Ireland. (Griffin M.) UCD Beacon Hospital Academy, Ireland. CORRESPONDENCE ADDRESS C. Anderson, UCD School of Medicine and Medical Science, Ireland. SOURCE Irish Journal of Medical Science (2017) 186:9 Supplement 1 (S355-S356). Date of Publication: 1 Sep 2017 CONFERENCE NAME 41st Annual Meeting of the Irish Endocrine Society CONFERENCE LOCATION Dublin, Ireland CONFERENCE DATE 2017-10-13 to 2017-10-14 ISSN 1863-4362 BOOK PUBLISHER Springer London ABSTRACT Immune Related Adverse Events (iRAEs) of the endocrine system are commonly recognised in Ipilimumab treatment (an anti-CTLA-4 antibody). Their frequency with programmed cell death (PD-1) receptor agents remains incompletely characterised. We present a case of Pembrolizumab-induced hypophysitis in a 47 yo. male with melanoma (M). Initial diagnosis ofMin 2007, lymph node recurrence 2013. He then entered adjuvant clinical trial of Vemurafenib versus placebo (patient unblined to placebo arm). In 2015 he presented with oligometastatic M1a disease and received 4 courses of Ipilimumab. This was complicated by a sarcoidosis-type reaction and erythema nodosum.Due to progression of M he proceeded to Pembrolizumab therapy. TSH fell from 0.988 to 0.1mIU/ml with fT4 13.43pmol/L pre vs 15.33pmol/L post 3 cycles.MRI pituitary was normal. He was asymptomatic with normal synacthen test (post stimulation cortisol 570nmol/L) and normal GCT for cortisol + Growth hormone. Thyroid USS and uptake scan were normal, TPO and TRAb negative. TSH recovered over 5 days reaching 2.92mIU/ml. Diagnosis: Grade 2 hypophysitis. 10 days later he re-presented with severe headache and TSH was 0.045. He received pulse iv steroids then po steroids as per protocol for Grade 3 hypophysitis. While he developed deficiencies in thyroid and sex hormones requiring temporary supplementation he ultimately had a full recovery in regard to his pituitary function.While hypothyroidism is noted commonly in patients receiving Pembrolizumab, hypophysitis is rare. The recognition and management of hypopituitarism particularly potential adrenal insufficiency is increasingly important for endocrine management of oncology patients. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS adjuvant endogenous compound growth hormone hydrocortisone ipilimumab placebo sex hormone tetracosactide thyrotropin vemurafenib EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis EMTREE MEDICAL INDEX TERMS adrenal insufficiency adult adverse drug reaction cancer recurrence case report clinical trial controlled clinical trial controlled study diagnosis drug therapy erythema nodosum headache human hypophysis function hypopituitarism hypothyroidism lymph node male melanoma nuclear magnetic resonance imaging oncology relapse remission sarcoidosis side effect CAS REGISTRY NUMBERS growth hormone (36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6) hydrocortisone (50-23-7) ipilimumab (477202-00-9) pembrolizumab (1374853-91-4) tetracosactide (16960-16-0) thyrotropin (9002-71-5) vemurafenib (918504-65-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618558225 DOI 10.1007/s11845-017-1670-4 FULL TEXT LINK http://dx.doi.org/10.1007/s11845-017-1670-4 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 27 TITLE Ipilimumab induced hypophysitis, pathogenesis and review of current literatures AUTHOR NAMES Okiro J. McHugh C.M. AUTHOR ADDRESSES (Okiro J.; McHugh C.M.) Department of Diabetes and Endocrinology, Sligo University Hospital, Sligo, Ireland. CORRESPONDENCE ADDRESS J. Okiro, Department of Diabetes and Endocrinology, Sligo University Hospital, Sligo, Ireland. SOURCE Irish Journal of Medical Science (2017) 186:9 Supplement 1 (S379). Date of Publication: 1 Sep 2017 CONFERENCE NAME 41st Annual Meeting of the Irish Endocrine Society CONFERENCE LOCATION Dublin, Ireland CONFERENCE DATE 2017-10-13 to 2017-10-14 ISSN 1863-4362 BOOK PUBLISHER Springer London ABSTRACT Ipilimumab is an anti-CTLA-4 monoclonal antibody licensed for metastatic melanoma, inhibiting CTLA-4 receptors on T-cells, enhancing immune response. Ipilimumab has been associated with immune related adverse events (irAEs). Hypophysitis accounts for 1-6% of Ipilimumab associated irAEs. A 70-year-old female with metastatic malignant melanoma presented with anorexia, malaise and confusion two weeks after her fourth dose of ipilimumab. She had a serum sodium of 124 mmol/L on PPI and SSRI which were stopped and she was fluid restricted to 1.5 litres. Her urinary sodium was 65. Serum cortisol was 19nmol/L with no history of steroid use. A short synacthen test demonstrated a cortisol rise from 18nmol/L at baseline to 176nmol/L at 90 minutes. But a glucagon stimulation test showed a baseline cortisol of19nmol/L which rose to 20nmol/L at 120 minutes, GH rose to maximum <0.3mIU/L during the test. Her FSH and LH were low at 5.8 mIU/ ml /0.4 mIU/ml respectively, oestradiol undetectable, TSH inappropriately low at 0.5 for T4 of 6.1. ACTH was relatively low at 3.2 pmol/L (1.1-13.2).MRI pituitary was normal. She was commenced on dexamethasone 0.75 mgs od pending glucagon test and is currently well and continues on 0.75 mgs to date. 6 months later TSH has returned to normal 0.71uIU/ml (T4 19.2 pmol/L), Na 137pmol/L, and repeat glucagon test is pending. The pathogenesis of ipilimumab induced hypophysitis (IIH) is not clearly understood. Studies have suggested checking anti-CTLA-4 antibodies which seem to be predictive in small studies but this is not currently routinely available. A high index of suspicion is important. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticotropin cytotoxic T lymphocyte antigen 4 antibody dexamethasone endogenous compound estradiol glucagon hydrocortisone serotonin uptake inhibitor sodium tetracosactide thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis EMTREE MEDICAL INDEX TERMS adverse drug reaction aged anorexia case report female human human tissue hydrocortisone blood level liquid malaise melanoma nuclear magnetic resonance imaging provocation test side effect sodium blood level sodium urine level CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) dexamethasone (50-02-2) estradiol (50-28-2) glucagon (11140-85-5, 62340-29-8, 9007-92-5) hydrocortisone (50-23-7) ipilimumab (477202-00-9) sodium (7440-23-5) tetracosactide (16960-16-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618558056 DOI 10.1007/s11845-017-1670-4 FULL TEXT LINK http://dx.doi.org/10.1007/s11845-017-1670-4 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 28 TITLE Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model AUTHOR NAMES Starbuck K. McGray R. Masoumi-Moghaddam S. Francois A. Odunsi K. Zsiros E. AUTHOR ADDRESSES (Starbuck K.; McGray R.; Masoumi-Moghaddam S.; Francois A.; Odunsi K.; Zsiros E.) Roswell Park Cancer Institute, Buffalo, United States. CORRESPONDENCE ADDRESS K. Starbuck, Roswell Park Cancer Institute, Buffalo, United States. SOURCE Cancer Research (2017) 77:13 Supplement 1. Date of Publication: 1 Jul 2017 CONFERENCE NAME American Association for Cancer Research Annual Meeting 2017 CONFERENCE LOCATION Washington, DC, United States CONFERENCE DATE 2017-04-01 to 2017-04-05 ISSN 1538-7445 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patients presenting with advanced stage disease. Immune check point blockade showed modest clinical response in patient with recurrent ovarian cancer, thus additional therapeutic strategies for combination therapy are needed. As chemokines and their receptors drive both immune cell migration and tumor growth, angiogenesis and metastasis formation, they are an attractive target for combinatorial cancer therapy. CXCR4 is the most highly expressed chemokine receptor in advanced stage high grade serous ovarian cancer, thus the objective of this study was to evaluate the efficacy of a novel oral small molecule CXCR4 inhibitor (X4-136) alone and in combination with immune checkpoint inhibition and the anti-angiogenic agent bevacizumab, and characterize the changes in circulating immune cells during treatment in murine ovarian cancer model. The ID8 cell line was used in C57BL/6J mice to establish an immune competent murine model and to compare single agent and combination therapy with oral X4-136 CXCR4 inhibitor, bevacizumab, and anti-PD1. During treatment blood sampling was performed and immune cells were analyzed by flow cytometry. Our results demonstrated that single agent therapies alone with either drug had no significant effect on tumor progression or survival. Combination therapy with the CXCR4 inhibitor and anti-PD1 improved survival compared to control animals and the other combination therapy groups. The addition of bevacizumab to the dual combination did not further prolong survival. Analysis of circulating immune cells revealed elevations in CD11b+Ly6C+ and the ratio of CD11b+Ly6C+ to CD11b+Ly6G+ in groups treated with the CXCR4 inhibitor, indicating an increase in circulating myeloid cells. Bevacizumab had no activity in this mouse model as a single agent, and did not have synergistic effect in combination therapy. For the first time we demonstrated that novel CXCR4 inhibitor X4-136 in combination therapy with anti-PD1 showed improved survival in murine ovarian cancer model. CXCR4 blockade increased the proportion of circulating myeloid cells during active treatment, thus further investigation into this novel therapeutic approach is warranted. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) chemokine receptor CXCR4 EMTREE DRUG INDEX TERMS bevacizumab endogenous compound EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) mouse model ovary cancer EMTREE MEDICAL INDEX TERMS animal cell animal experiment animal model blood sampling bone marrow cell C57BL 6 mouse cancer staging cancer survival cell line comparative effectiveness controlled study drug combination drug therapy female flow cytometry immunocompetent cell mouse nonhuman tumor growth CAS REGISTRY NUMBERS bevacizumab (216974-75-3) chemokine receptor CXCR4 (188900-71-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L618567515 DOI 10.1158/1538-7445.AM2017-956 FULL TEXT LINK http://dx.doi.org/10.1158/1538-7445.AM2017-956 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 29 TITLE Adrenal insufficiency secondary to ipilimumab induced hypophysitis: The Northern Irish experience AUTHOR NAMES Todd A. Wallace I. Thiraviaraj A. Oladipo B. Nugent A. AUTHOR ADDRESSES (Todd A.; Wallace I.; Nugent A.) Department of Endocrinology and Diabetes, Belfast City Hospital, Belfast, United Kingdom. (Thiraviaraj A.) Department of Endocrinology and Diabetes, Altnagelvin Area Hospital, Londonderry, United Kingdom. (Oladipo B.) Regional Cancer Centre, Belfast City Hospital, Belfast, United Kingdom. CORRESPONDENCE ADDRESS A. Todd, Department of Endocrinology and Diabetes, Belfast City Hospital, Belfast, United Kingdom. SOURCE Irish Journal of Medical Science (2016) 185:7 Supplement 1 (S409). Date of Publication: 1 Oct 2016 CONFERENCE NAME 40th Annual Meeting of the Irish Endocrine Society CONFERENCE LOCATION Belfast, United Kingdom CONFERENCE DATE 2016-10-14 to 2016-10-15 ISSN 1863-4362 BOOK PUBLISHER Springer London ABSTRACT Ipilimumab is a fully humanised monoclonal antibody used in the treatment of malignant melanoma. Endocrinopathies are amongst its known side-effects, in particular hypophysitis and thyroiditis. We describe our regional experience of 7 cases of hypophysitis (4 male, 3 female with a mean age of 62.1 years). Cases presented with a spectrum of symptoms ranging from lethargy and headache to adrenal crisis. All patients presented after cycle 3 or 4. All patients had low serum cortisol concentration or undetectable ACTH and secondary hypothyroidism. In addition 5 patients had suppressed gonadotropins and 2 suppressed prolactin levels. In contrast to the literature only one patient demonstrated the classical finding of an enlarged pituitary or pituitary stalk. The first 4 patients were managed with high dose steroids in the form of prednisolone 1 mg/kg, slowly weaned to replacement doses. Levothyroxine and testosterone replacement was prescibed as required. Pituitary function was not regained in these 4 patients and 2 patients experienced significant deterioration in pre-existing type 2 diabetes control, 1 requiring admission. The subsequent 3 patients were treated with replacement hydrocortisone, levothyroxine and testosterone as appropriate. Outcomes in both groups were similar but the replacement dose group did not experience side-effects associated with high dose steroids. From our experience high dose steroid replacement does not improve pituitary recovery and therefore replacement hydrocortisone is more appropriate and appears to offer the same outcome. While only a small proportion of patients will suffer hypophysitis it is important to raise awareness as prompt diagnosis and treatment is potentially life-saving. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticotropin endogenous compound gonadotropin hydrocortisone levothyroxine prednisolone prolactin testosterone EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency hypophysitis EMTREE MEDICAL INDEX TERMS adult adverse drug reaction androgen therapy awareness clinical article clinical trial deterioration diabetes control diagnosis drug combination drug megadose drug therapy female gene expression gene inactivation headache human human tissue hydrocortisone blood level hypophysis function hypothyroidism lethargy male middle aged non insulin dependent diabetes mellitus normal human pituitary stalk side effect symptom CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) gonadotropin (63231-54-9) hydrocortisone (50-23-7) ipilimumab (477202-00-9) levothyroxine (51-48-9) prednisolone (50-24-8) prolactin (12585-34-1, 50647-00-2, 9002-62-4) testosterone (58-22-0) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617932974 DOI 10.1007/s11845-016-1482-y FULL TEXT LINK http://dx.doi.org/10.1007/s11845-016-1482-y COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 30 TITLE Treatment with nivolumab results in asymptomatic thyroiditis followed by severe hypothyroidism AUTHOR NAMES Yu D. Kapoor A. AUTHOR ADDRESSES (Yu D.) Endocrinology and Metabolism, Stony Brook University Hospital, Stony Brook, United States. (Kapoor A.) Northport Veterans Affairs Hospital, Northport, United States. CORRESPONDENCE ADDRESS D. Yu, Endocrinology and Metabolism, Stony Brook University Hospital, Stony Brook, United States. SOURCE Thyroid (2016) 26 Supplement 1 (A95). Date of Publication: 2016 CONFERENCE NAME 86th Annual Meeting of the American Thyroid Association CONFERENCE LOCATION Denver, CO, United States CONFERENCE DATE 2016-09-21 to 2016-09-25 ISSN 1050-7256 BOOK PUBLISHER Mary Ann Liebert Inc. ABSTRACT Nivolumab is a monoclonal antibody against Programmed Cell Death-1 (PD-1) and has current FDA approval for the treatment of metastatic melanoma and advanced non-small cell lung carcinoma. With prolonged use, there may be associated thyroid adverse effects such as hypothyroidism, hyperthyroidism and thyroiditis. We report a case of asymptomatic thyroiditis followed by severe hypothyroidism associated with nivolumab use. A 71-year-old man with hypertension, hyperlipidemia, impaired fasting glucose, and remote history of prostate carcinoma treated with radical prostatectomy, was diagnosed with poorly differentiated metastatic lung adenocarcinoma. He was initially treated with carboplatin and taxol, but due to severe adverse effects, he was given nivolumb instead. After 2 months of therapy with nivolumab, he was found to have thyroiditis, with a TSH of 0.07 mU/L (0.35-5.5), free thyroxine index of 10.2 μg/dL (5.93-13.3) and total of T4 12.15 μg/dL (6.1-12.2). Thyroid stimulating immunoglobulins were negative, but he had positive thyroid peroxidase antibodies at 89 IU/mL (0-34). Physical exam was revealed a non-tender thyroid. Chart review also demonstrated 15 years of stable thyroid function tests. Four months after starting nivolumab, he developed severe hypothyroidism (TSH 84.2 mU/L, total T4 4.56 μg/dL and Free T4 0.3 ng/dL (0.6-1.2 ng/ mL)) with the only complaint of fatigue and normal physical findings. He was subsequently started on levothyroxine. Treatment with nivolumab has been associated with the development of various autoimmune phenomenon. This case highlights an example manifested by very rapid progression to severe hypothyroidism, which initially began as thyroiditis after 2 months of therapy. As the number of patients being treated with nivolumab increases, clinicians need to be aware of the increasing potential for varying types of thyroid disease that can occur with prolonged treatment. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS carboplatin endogenous compound levothyroxine paclitaxel thyroid peroxidase antibody thyroid stimulating immunoglobulin thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypothyroidism thyroiditis EMTREE MEDICAL INDEX TERMS adenocarcinoma adverse drug reaction aged case report clinical trial diagnosis drug combination drug therapy fatigue free thyroxine index glucose blood level human hyperlipidemia hypertension lung metastasis male medical record review prostate carcinoma prostatectomy side effect thyroid function test CAS REGISTRY NUMBERS carboplatin (41575-94-4) levothyroxine (51-48-9) nivolumab (946414-94-4) paclitaxel (33069-62-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617933545 DOI 10.1089/thy.2016.29022.abstracts FULL TEXT LINK http://dx.doi.org/10.1089/thy.2016.29022.abstracts COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 31 TITLE Nivolumab-induced thyroiditis in a patient with metastatic renal cell carcinoma AUTHOR NAMES Panach K. Oo Y. AUTHOR ADDRESSES (Panach K.) UTSW, Dallas, United States. (Oo Y.) VA, Dallas, United States. CORRESPONDENCE ADDRESS K. Panach, UTSW, Dallas, United States. SOURCE Thyroid (2016) 26 Supplement 1 (A14). Date of Publication: 2016 CONFERENCE NAME 86th Annual Meeting of the American Thyroid Association CONFERENCE LOCATION Denver, CO, United States CONFERENCE DATE 2016-09-21 to 2016-09-25 ISSN 1050-7256 BOOK PUBLISHER Mary Ann Liebert Inc. ABSTRACT Nivolumab is one of the human immunoglobulin G4 (IgG4) monoclonal antibody agents (anti-PD-1-mAb). It selectively inhibits programmed cell death-1 (PD-1) of T cells leading to unrestrained T cell activation and anti-tumor activity. It can also cause an activation of T cells against host cells and immune-mediated endocrine adverse events. Nivolumab associated auto-immune diabetes mellitus, hypophysitis, thyroid and adrenal dysfunction have been reported. Nivolumab is currently approved for the treatment of melanoma, metastatic non-small cell lung cancer, and advanced renal cell cancer. We report a case of Nivolumab-induced thyroid dysfunction in a 58-year-old man with metastatic clear cell renal cell carcinoma. The patient had normal thyroid function tests (TFTs) prior to treatment with Nivolumab. He presented with symptoms of hyperthyroidism 28 days after receiving the first dose of Nivolumab. TFTs showed low TSH and high free T4 of 3.89 ng/ dl (ref: 0.60 - 1.60 ng/dL). Hyperthyroidism symptoms quickly resolved with symptomatic treatment. Thyroid scan showed an uptake of 1.1%, suggestive of thyroiditis. He quickly became hypothyroid with a TSH of 94 mIU/ml (ref: 0.34 - 5.6 uIU/mL) and low FT4, 4 weeks after initial manifestations of thyroid dysfunction. Normalization of TFTs was achieved with Levothyroxine. The reported incidence and onset of thyroid dysfunction (hyperthyroidism and hypothyroidism, or autoimmune thyroiditis) after initiation of anti-PD-1-mAbs is 1.8 - 9% and 2.8 months (range: 15 days - 13.8 months), respectively. Hypothyroidism occurred more frequently in patients receiving combination therapy with the cytotoxic T-lymphocyte antigen 4 monoclonal antibody, Ipilimumab. The occurrence rate of hypothyroidism varied with underlying cancers (22% in melanoma patients vs 8%in renal cell cancer patients). Spontaneous resolution of thyroid dysfunction in mild cases has been reported but some developed permanent hypothyroidism. Discontinuation of Nivolumab therapy is rarely necessary. In summary, our case highlights the need to obtain baseline and interval TFTs in patients receiving Nivolumab to have an early diagnosis of immune-related thyroid dysfunction. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 endogenous compound ipilimumab levothyroxine programmed death 1 receptor thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune thyroiditis kidney metastasis EMTREE MEDICAL INDEX TERMS adrenal cortex insufficiency adult adverse drug reaction cancer patient case report clinical trial controlled study diabetes mellitus drug combination drug therapy early diagnosis free thyroxine index human hyperthyroidism hypophysitis hypothyroidism male melanoma middle aged non small cell lung cancer palliative therapy remission side effect symptom thyroid function test CAS REGISTRY NUMBERS ipilimumab (477202-00-9) levothyroxine (51-48-9) nivolumab (946414-94-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617933719 DOI 10.1089/thy.2016.29022.abstracts FULL TEXT LINK http://dx.doi.org/10.1089/thy.2016.29022.abstracts COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 32 TITLE Use of immune checkpoint inhibitors induces an immune mediated hypophysitis AUTHOR NAMES Mansoor S. Hall R. Mihalek A. AUTHOR ADDRESSES (Mansoor S.; Hall R.; Mihalek A.) University of Virginia, Charlottesville, United States. CORRESPONDENCE ADDRESS S. Mansoor, University of Virginia, Charlottesville, United States. SOURCE American Journal of Respiratory and Critical Care Medicine (2017) 195. Date of Publication: 2017 CONFERENCE NAME American Thoracic Society International Conference, ATS 2017 CONFERENCE LOCATION Washington, DC, United States CONFERENCE DATE 2017-05-19 to 2017-05-24 ISSN 1535-4970 BOOK PUBLISHER American Thoracic Society ABSTRACT Introduction: Treatment with immune checkpoint inhibitors (ICPIs) such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody (ipilimumab) and the anti-programmed cell death-protein 1 (PD-1) antibody (nivolumab)are utilized in multiple malignancies with improved outcomes, particularly in advanced melanoma1.Due to the loss of T-cell inhibition, self tolerance is impaired resulting in an augmented immune-related inflammation of normal tissueswith subsequent immune-related adverse events (irAEs)1. Case report: A 46-year-old female with a past medical history of melanoma metastatic to multiple soft tissues and lymph nodes, treated with ipilimumab and nivolumab after an incomplete response with pembrolizumab presented with a two day history of fever, generalized weakness, headache, non-bloody non bilious emesis, generalized abdominal pain, non-bloody diarrhea, and a centralized maculopapular rash.At presentation, she was afebrile, hypotensive without a response to fluid resuscitation, and tachycardic.She did not appear ill and was without signs of an acute abdomen.Vasopressors and stress dose steroids were initiated with resolution of hypotension.Hyponatremia, thrombocytopenia and transaminitis were noted without leukocytosis. An extensive infectious work up was negative.A random cortisol level was 5ug/dL (4-19 ug/dL), an ACTH level was 6pg/mL (9 - 52 pg/mL), Prolactin 1.6 ng/mL (2.0 - 30.0 ng/mL), TSH, free T4, and free T3 were 0.05mlU/L (0.45 - 4.50 mIU/L), 0.91ng/dL (0.7 - 1.5 ng/dL), and 1.7pg/dL (2.3 - 4.2 pg/mL), respectively. Computated tomographic imaging of the head revealed prominence of the pituitary. Confirmatory magnetic resonance imaging (MRI) of the head revealed thickening and enlargement of the pituitary gland and infundibulum consistent with a clinical diagnosis of Ipilimumab-associated hypophysitis. Based on the above findings, the patient was diagnosed with an immune-related adverse event from ICPI therapy highlighted by hypophysitis causing primary adrenal insufficiency, thyroid dysfunction, colitis, hepatitis and skin toxicity.She received solumedrol 2mg/kg IV BID with improvement of symptoms over next week.She also received levothyroxine and was discharged home on a prednisone taper. Discussion: ICPIs induced irAEs should be considered in patients presenting with clinical evidence of multi-organ inflammation and shock.Hepatitis (19%), diarrhea (9%) and colitis (8%) are the most commonly reported adverse events1. However, endocrinopathies such as hypophysitis and hypothyroidism can also occur2. With increased application of ICPIs to an ever-growing list of malignancies (including non-small cell lung carcinoma), having a high index of suspicion for this clinical entity is critical for early diagnosis and treatment. EMTREE DRUG INDEX TERMS antihypertensive agent corticotropin cytotoxic T lymphocyte antigen 4 antibody endogenous compound hydrocortisone ipilimumab levothyroxine methylprednisolone sodium succinate nivolumab pembrolizumab prolactin thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis EMTREE MEDICAL INDEX TERMS acute abdomen Addison disease adult adverse drug reaction asthenia case report chemical stress colitis diagnosis diarrhea drug combination drug therapy early diagnosis female fever fluid resuscitation free liothyronine index free thyroxine index headache hepatitis human hypertransaminasemia hyponatremia hypotension hypothyroidism leukocytosis lymph node maculopapular rash medical history melanoma middle aged non small cell lung cancer nuclear magnetic resonance imaging organ side effect skin toxicity soft tissue symptom tachycardia thrombocytopenia vomiting CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) levothyroxine (51-48-9) methylprednisolone sodium succinate (2375-03-3, 2921-57-5) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) prolactin (12585-34-1, 50647-00-2, 9002-62-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617709391 DOI 10.1164/ajrccm-conference.2017.B57 FULL TEXT LINK http://dx.doi.org/10.1164/ajrccm-conference.2017.B57 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 33 TITLE Combined FDG and NaF PET/CT study in patients (pts) with metastatic genitourinary tumors (mGU) treated with cabozantinib + nivolumab +/-ipilimumab (CaboNivo+/-Ipi) AUTHOR NAMES Lin J. Mortazavi A. Stein M.N. Pal S.K. Davarpanah N.N. Nadal R.M. Francis D.C. Berniger M.A. Monk P. Kempf J. Becker M. Sokol L. McKinney Y. Knopp M.V. Wright C. Jung A. Choyke P.L. Mena E. Lindenberg L. Apolo A.B. AUTHOR ADDRESSES (Lin J.; Mortazavi A.; Stein M.N.; Pal S.K.; Davarpanah N.N.; Nadal R.M.; Francis D.C.; Berniger M.A.; Monk P.; Kempf J.; Becker M.; Sokol L.; McKinney Y.; Knopp M.V.; Wright C.; Jung A.; Choyke P.L.; Mena E.; Lindenberg L.; Apolo A.B.) Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Arthur G. James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; City of Hope Comprehensive Cancer Center, Duarte, CA; National Institutes of Health, Bethesda, MD; Leidos Biomedical Inc., National Cancer Institute, Bethesda, MD; The Ohio State University, Columbus, OH; Rutgers Robert Wood Johnson Medical School, Newark, NJ CORRESPONDENCE ADDRESS J. Lin, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: The primary objective of the study is to assess the feasibility of obtaining combined FDG and NaF PET/CT in detecting soft-tissue and bone metastatic disease in mGU pts treated with CaboNivo+/-Ipi. Methods: Pts in this single-arm, multicenter, phase I trial had FDG PET/CT followed by NaF PET/CT within 1 hour, at baseline and 8 weeks. The number and location of metastatic lesions on FDG PET/CT and on NaF PET/CT were captured. Lesions were considered positive when there was focal abnormal radiotracer uptake with CT correlation. We analyzed soft tissue and bone lesions distribution and the concordance of baseline metastatic bone disease. Results: From 7/14/15 to 9/9/16, 27 pts (urothelial carcinoma N = 11, bladder squamous cell carcinoma N = 2, sarcomatoid renal cancer N = 1, sertoli cell N = 1, germ cell tumor N = 4, trophoblastic testicular cancer N = 1, urachal N = 4, castrate-resistant prostate cancer N = 2, prostate neuroendocrine N = 1) had scans. Median age was 55 (range 35-75 yr), 24 (89%) were male. Pts completed the dual PET/CTs on the same day (imaging time 3-4 hours) without complications. On FDG, the distribution of 340 lesions were lymph node 41%, bone 35%, lung 18%, liver 11%, soft tissue 4%, kidney 0.6%, adrenal 0.3%, spleen 0.3%, pancreas 0.3%. On NaF, the distribution of 130 lesions was spine 33%, rib 16%, pelvis 13%, femur 10%, scapula 9%, sacrum 8%, skull 5%, humerus 4%, sternum 3%, manubrium 2%, clavicle 2%. Of the 130 lesions on FDG/NaF PET/CT, 38% were not seen on initial FDG. The combination of the two tracers did not affect the quality of the PET/CTs given distinct radiotracer uptake in the anatomical locations with no distortions. Residual FDG activity on combined FDGNaF images required background intensity to be adjusted to delineate focal radiotracer uptake. There was no difficulty in identifying metastatic lesions, and no instances of prior FDG uptake affecting the determination of metastatic disease. Conclusions: Combination FDG-NaF PET/CT is a feasible imaging modality that offers convenience to pts without compromising detection of metastatic disease in mGU pts. FDG alone detected fewer bone lesions than combined FDG-NaF PET/CT. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS endogenous compound tracer EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) positron emission tomography-computed tomography prostate cancer testis cancer EMTREE MEDICAL INDEX TERMS adrenal gland adult aged bone lesion bone metastasis clavicle clinical trial complication drug combination drug therapy feasibility study female femur germ cell tumor human humerus imaging kidney cancer liver lung lymph node major clinical study male manubrium pancreas pelvis rib sacrum scapula Sertoli cell soft tissue spine spleen squamous cell carcinoma tissue injury transitional cell carcinoma trophoblast urachus CAS REGISTRY NUMBERS ipilimumab (477202-00-9) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617537817 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 34 TITLE Incidence of thyroid function test abnormalities in patients receiving immune checkpoint inhibitor therapy for cancer: A single institution retrospective review AUTHOR NAMES Patel N.S. Oury A. Bazhenova L. Daniels G.A. Patel S.P. AUTHOR ADDRESSES (Patel N.S.; Oury A.; Bazhenova L.; Daniels G.A.; Patel S.P.) University of California, San Diego, San Diego, CA; Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, CA; University of California San Diego Moores Cancer Center, La Jolla, CA CORRESPONDENCE ADDRESS N.S. Patel, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: With the advent of immune-checkpoint inhibitor (ICI) therapy, thyroid function test abnormalities (TFTA) are common with reported incidence range of 2-15%. Our aim was to describe the incidence of TFTAs retrospectively in patients (pts) on ICI therapy. Methods: 285 pts reviewed (178 male, 107 female; ages 16-94) of which 218 had no baseline TFTA, 61 had baseline TFTAs, and 6 had thyroidectomy (excluded). Pts received at least one dose of ipilimumab (I) and/or nivolumab (N) or pembrolizumab (P). Post-treatment TFTA was classified according to definitions of thyroid abnormalities when possible. Results: A total of 35% (76/218) pts had new onset TFTAs on ICI. Of note, 70.5% (43/61) had baseline TFTA that were exacerbated by ICI. Median time to new onset or exacerbated baseline TFTA were 46 & 33 days respectively. Of note, 65% (20/31) of pts on both I+N had new onset TFTA, compared to 31.3% (15/48) with I, 31.5% (28/89) N, 26% (13/50) P. Conclusions: Incidence of TFTAs with ICI was higher than expected in our pts. Pts with baseline TFTA and/or I+N combination therapy had higher incidence of TFTA than one agent ICI therapy. In conclusion, we recommend more frequent evaluation of TFT in the first two months, especially in those with baseline TFTA. (Table Presented). EMTREE DRUG INDEX TERMS ipilimumab nivolumab pembrolizumab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) congenital malformation malignant neoplasm retrospective study thyroid function test EMTREE MEDICAL INDEX TERMS adolescent clinical trial drug combination drug therapy female human major clinical study male thyroid disease thyroidectomy CAS REGISTRY NUMBERS ipilimumab (477202-00-9) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617537561 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 35 TITLE Dynamics of immune-mediated thyroid dysfunction in patients with advanced renal cell carcinoma receiving checkpoint inhibitor therapy AUTHOR NAMES Osorio J.C. Patil S. Coskey D.T. Carlo M.I. Feldman D.R. Hellmann M.D. Voss M.H. AUTHOR ADDRESSES (Osorio J.C.; Patil S.; Coskey D.T.; Carlo M.I.; Feldman D.R.; Hellmann M.D.; Voss M.H.) Weill Cornell Medical College, New York, NY; Memorial Sloan- Kettering Cancer Center, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY CORRESPONDENCE ADDRESS J.C. Osorio, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Checkpoint inhibitors (CPI) are quickly gaining relevance in the management of metastatic renal cell carcinoma (RCC). Treatment is generally well tolerated, but immune-induced thyroid dysfunction (TD) is reported in up to 10% of patients (pts) across trials. The dynamics of this phenomenon are undefined; hence there are no proposed standards for endocrine surveillance on therapy. Here we report on a cohort of RCC pts treated with CPI at Memorial Sloan Kettering Cancer Center with serial prospective assessment of thyroid function on therapy. Methods: Thyroid function tests (TFT) were assessed at baseline and serially on therapy. We recorded trends for hyper- and hypothyroidism and determined median time to development of TD by standard statistical methods. T4 replacement therapy was investigated by individual chart review. The association of TD with outcomes on CPI therapy was assessed by non-parametric tests. Results: Of 59 pts with serial TFT assessment, 20 were hypothyroid and 39 were euthyroid at baseline. 50% of previously hypothyroid pts required adjustment of T4 dosage. Thirteen of 39 euthyroid pts (36%) developed new TD requiring thyroid replacement. TD occurred early (median time to onset: 1.4 months, range 0.9-9.6), and in six of the 13 pts (46%), transient thyroiditis preceded hypothyroidism. None of the pts with thyroiditis required treatment, and the median duration from onset of thyroiditis to development of hypothyroidism was 1.5 months (range 0.7-2.8). All pts with hypothyroidism required replacement therapy; none required discontinuation of immunotherapy due to TD. TD was not associated with difference in objective response rate (fisher's exact, p = 0.163), regression in target lesions (wilcoxon ranksum, p = 0.135), or PFS (log rank p = 0.8214). Conclusions: TD is common in RCC pts receiving CPI therapy. In this cohort, onset of TD was early, thyroiditis was always transient, and no new cases were detected beyond 10 months. Confirming these findings in larger cohorts will provide meaningful data to guide management of TD when using this new class of agents outside of clinical trials. EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female hypothyroidism kidney carcinoma male EMTREE MEDICAL INDEX TERMS clinical trial human immunotherapy major clinical study medical record review nonparametric test substitution therapy thyroid function test thyroiditis LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617537300 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 36 TITLE A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-) AUTHOR NAMES Garcia I.M. Grande E. Garcia-Carbonero R. Lopez C. Teule A. Capdevila J. AUTHOR ADDRESSES (Garcia I.M.; Grande E.; Garcia-Carbonero R.; Lopez C.; Teule A.; Capdevila J.) Vall d'Hebron University Hospital Institute of Oncology (VHIO), Barcelona, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Marqués de Valdecilla University Hospital, Santander, Spain; Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Spain CORRESPONDENCE ADDRESS I.M. Garcia, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) durvalumab ticilimumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 endogenous compound platinum somatostatin derivative EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) controlled study female lung male pancreas islet cell tumor EMTREE MEDICAL INDEX TERMS blood cancer epidemiology chemotherapy clinical trial comparative effectiveness controlled clinical trial disease control drug combination drug therapy follow up gastrointestinal tract human immunotherapy major clinical study overall survival pharmacokinetics phase 2 clinical trial probability progression free survival remission response evaluation criteria in solid tumors retreatment safety tumor growth CAS REGISTRY NUMBERS durvalumab (1428935-60-7) platinum (7440-06-4) ticilimumab (745013-59-6) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617435711 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 37 TITLE Safety findings from FORWARD II: A phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer AUTHOR NAMES O'Malley D.M. Moore K.N. Vergote I. Martin L.P. Gilbert L. Martin A.G. Nepert D.L. Ruiz-Soto R. Birrer M.J. Matulonis U.A. AUTHOR ADDRESSES (O'Malley D.M.; Moore K.N.; Vergote I.; Martin L.P.; Gilbert L.; Martin A.G.; Nepert D.L.; Ruiz-Soto R.; Birrer M.J.; Matulonis U.A.) The Ohio State University College of Medicine, Columbus, OH; University of Oklahoma Health Sciences Center, Oklahoma City, OK; BGOG and University of Leuven, Leuven Cancer Institute, Leuven, Belgium; Fox Chase Cancer Center, Philadelphia, PA; McGill University Health Centre, Montréal, QC, Canada; Grupo Español de Investigación en Cáncer de Ovario (GEICO) and the University of Texas MD Anderson Cancer Center, Madrid, Spain; ImmunoGen, Inc., Waltham, MA; Massachusetts General Hospital, Boston, MA CORRESPONDENCE ADDRESS D.M. O'Malley, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background:FORWARD II is a phase 1b study of the FRα-targeting ADC, mirvetuximab soravtansine (IMGN853), in combination with bevacizumab (BEV), carboplatin, PLD, or pembrolizumab in adults with FRα-positive EOC, primary peritoneal, or fallopian tube tumors (NCT02606305). Methods:The escalation stage of this trial evaluated the safety and tolerability of IMGN853 as part of 4 combination regimens: IMGN853 + BEV; + carboplatin; + PLD; and + pembrolizumab. IMGN853 was administered in combination on Day 1 of a 21 (BEV or carboplatin) or 28-day cycle (PLD). Pembrolizumab escalation is continuing. The starting dose of IMGN853 was 5 mg/kg (adjusted ideal body weight, AIBW), one level lower than the recommended single agent phase 2 dose (RP2D; 6 mg/kg AIBW) defined in a first-in-human study (NCT01609556). Adverse events (AEs) were evaluated by CTCAE v4.0. Results:46 pts enrolled in the first 3 cohorts. IMGN853 was escalated from 5 to 6 mg/kg. Carboplatin and PLD dosing were escalated from AUC4 to AUC5 and 30 to 40 mg/m2, respectively; BEV dosing remained constant at 15 mg/kg. Diarrhea, nausea, and fatigue were common across cohorts (all grades; 33-57%) and mostly low grade (i.e. ≤ 2), consistent with the IMGN853 safety profile from the earlier phase I monotherapy study. AEs of interest related to the combination agents were seen in each arm. For example, grade 1/2 proteinuria (36%) and grade 3 hypertension (21%) were only observed in the BEV combination. Thrombocytopenia (44%) and neutropenia (39%), grades 1-3, occurred most frequently in the carboplatin arm. Grade 3 anemia and vomiting (each 14%), as well as low grade (≤ 2) constipation (43%), were seen in the PLD cohort. Conclusions:The RP2D dose of IMGN853 was readily combined with the highest doses (as per protocol) of BEV, carboplatin, and PLD. The AE profiles for these combinations were manageable and as expected based on known profiles of each agent; importantly, no new safety signals were identified. Updated data from all 4 combination regimens will be presented. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody drug conjugate bevacizumab carboplatin doxorubicin folate receptor 1 mirvetuximab soravtansine pembrolizumab EMTREE DRUG INDEX TERMS endogenous compound EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) controlled study female male ovary cancer safety EMTREE MEDICAL INDEX TERMS adult adverse drug reaction anemia clinical article clinical trial constipation controlled clinical trial diarrhea drug combination drug megadose fatigue human hypertension ideal body weight monotherapy nausea neutropenia peritoneum tumor pharmacokinetics phase 1 clinical trial phase 2 clinical trial proteinuria side effect thrombocytopenia uterine tube tumor vomiting CAS REGISTRY NUMBERS bevacizumab (216974-75-3) carboplatin (41575-94-4) doxorubicin (23214-92-8, 25316-40-9) mirvetuximab soravtansine (1453084-37-1) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617434883 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 38 TITLE Efficacy/safety of epacadostat plus pembrolizumab in triple-negative breast cancer and ovarian cancer: Phase I/II ECHO-202 study AUTHOR NAMES Spira A.I. Hamid O. Bauer T.M. Borges V.F. Wasser J.S. Smith D.C. Clark A.S. Schmidt E.V. Zhao Y. Maleski J.E. Gangadhar T.C. AUTHOR ADDRESSES (Spira A.I.; Hamid O.; Bauer T.M.; Borges V.F.; Wasser J.S.; Smith D.C.; Clark A.S.; Schmidt E.V.; Zhao Y.; Maleski J.E.; Gangadhar T.C.) Virginia Cancer Specialists Research Institute, Fairfax, VA; The Angeles Clinic and Research Institute, Los Angeles, CA; Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; University of Colorado Denver, Aurora, CO; University of Connecticut Health Center, Farmington, CT; University of Michigan, Ann Arbor, MI; Abramson Cancer Center, Philadelphia, PA; Merck & Co., Inc., Kenilworth, NJ; Incyte Corporation, Wilmington, DE CORRESPONDENCE ADDRESS A.I. Spira, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Epacadostat is an oral, potent, and selective inhibitor of indoleamine 2,3-dioxygenase 1, a tryptophancatabolizing enzyme that induces immune tolerance via T-cell suppression and is associated with poor patient (pt) survival when overexpressed in some cancers. The ongoing, open-label, phase 1/2 (P1/2) ECHO-202/KEYNOTE-037 study is evaluating the efficacy, safety, and tolerability of epacadostat plus PD-1 inhibitor pembrolizumab (E + P) in pts with advanced/recurrent cancers. We report P1/2 study outcomes for triple-negative breast cancer (TNBC) pts and P2 outcomes for ovarian cancer (OVC; no P1) pts as of a 29OCT2016 data cutoff. Methods: Eligible pts were ≥18 years old with no prior checkpoint inhibitor treatment (tx); prior platinum/taxane tx was required for OVC pts. As part of P1 dose escalation, TNBC pts received E (300 mg BID) + P (200 mg Q3W). In P2, TNBC and OVC pts received E (100 mg BID) + P (200 mg Q3W). Response (RECIST v1.1) was assessed in evaluable pts. Safety and tolerability were assessed in pts with ≥1 dose of E + P. Results: A total of 39 pts with TNBC and 37 with OVC were enrolled. The majority of TNBC pts (56%, n = 22) and OVC pts (78%, n = 29) received ≥3 prior lines of tx. For TNBC pts, ORR (CR+PR) was 10% (n = 4; all PR) and DCR (CR+PR+SD) was 36% (n = 14; 10 SD); ORR and DCR for pts with ≤2 prior tx were 12% (n = 2) and 29% (n = 5), respectively, and for ≥3 prior tx were 9% (n = 2) and 41% (n = 9). For OVC pts, ORR was 8% (n = 3; all PR) and DCR was 35% (n = 13; 10 SD); ORR and DCR for pts with ≤2 prior tx were 13% (n = 1) and 25% (n = 2), and for ≥3 prior tx were 7% (n = 2) and 38% (n = 11). The most common TRAEs (≥15% of pts) were rash (18%), fatigue (15%), and nausea (15%) in the 39 TNBC pts, and fatigue (19%) in the 37 OVC pts. Grade ≥3 TRAEs occurred in 13% of TNBC pts (n = 5; none in > 1 pt) and 19% of OVC pts (n = 7; only rash occurred in > 1 pt [n = 3]). TRAEs led to discontinuation in 1 TNBC pt (grade 3 ascites) and 1 OVC pt (grade 2 arthralgia). Conclusions: E + P tx was generally well tolerated and showed antitumor activity consistent with previously reported P monotherapy in pts with advanced TNBC or OVC. Biomarker analysis is ongoing to characterize pt populations enrolled in this study. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) epacadostat pembrolizumab EMTREE DRUG INDEX TERMS biological marker endogenous compound platinum programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) controlled study female ovary cancer safety triple negative breast cancer EMTREE MEDICAL INDEX TERMS adult advanced cancer antineoplastic activity arthralgia ascites cancer patient cancer recurrence clinical article clinical trial comparative effectiveness controlled clinical trial drug combination drug therapy drug withdrawal fatigue human male monotherapy nausea pharmacokinetics phase 1 clinical trial phase 2 clinical trial rash response evaluation criteria in solid tumors young adult CAS REGISTRY NUMBERS epacadostat (1204669-58-8) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617450081 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 39 TITLE Immunologic and genomic characterization of high grade serous ovarian cancer (HGSOC) in patients (pts) treated with pembrolizumab (Pembro) in the phase II INSPIRE trial AUTHOR NAMES Colombo I. Lien S. Yang C. Clouthier D.L. Bonilla L. Cyriac S. Ethier J.-L. Lee Y.C. Kanjanapan Y. Mandilaras V. Dhani N.C. Butler M.O. Oza A.M. Quintos J. Chow H. Pugh T.J. Ohashi P.S. Siu L.L. Lheureux S. AUTHOR ADDRESSES (Colombo I.; Lien S.; Yang C.; Clouthier D.L.; Bonilla L.; Cyriac S.; Ethier J.-L.; Lee Y.C.; Kanjanapan Y.; Mandilaras V.; Dhani N.C.; Butler M.O.; Oza A.M.; Quintos J.; Chow H.; Pugh T.J.; Ohashi P.S.; Siu L.L.; Lheureux S.) Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada CORRESPONDENCE ADDRESS I. Colombo, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Checkpoint inhibitors have shown to be effective in different tumors and are under investigation in HGSOC. Methods: INSPIRE (NCT02644369) is a prospective multi-cohort study investigating tumor genomic and immune landscapes in pts treated with Pembro at 200 mg IV Q3W. Patients underwent tumor biopsy pre, ontreatment and at progression for DNA/RNA sequence, immune-profile, and PD-L1 expression by immunohistochemistry (IHC). Serial blood samples for immunophenotyping were collected. Correlative data are available for 6 pts: 3 with shrinkage in target lesion and 3 with progressive disease (PD). Results: At interim analysis as of January 2017, 18 pts with HGSOC have been enrolled and 16 have platinumresistant disease, with median 3 prior lines of treatment (range 1-7). Of 14 evaluable pts, best response by RECIST 1.1 was stable disease (SD) in 5 (36%) and PD in 9 (64%). Mean Tumor Proportion Score of PD-L1 by IHC (Qualtek) was 6.4% (range 0-30%). Grade 3/4 adverse events possibly related to Pembro were observed in 4/18 (22%) pts; none was fatal and the most common were fatigue and hyponatremia. Preliminary correlative data showed no significant change in CD4, CD8 and myeloid-derived suppressor cells in peripheral blood after Pembro treatment. Mean PD-1 expression on CD4 and CD8 T cells on baseline tumor tissue (measured as product of PD-1+ cells and the per cell expression of PD-1 [% of mean fluorescence intensity]) was significantly higher in pts with tumor shrinkage compared to pts with PD (CD4: 2658 vs 678, p = .02; CD8: 1999 vs 451, p = .048). Genomic analysis of baseline tumor tissue was available for 3 pts with tumor shrinkage and 2 with PD. Mean mutation burden was higher for pts with tumor shrinkage (2.38 vs 1.0 mutations/Mb covered). The pt with the longest SD in our cohort (6 months) had the highest mutation burden (2.72), including somatic POLE (c.6331-6C > G) and germline BRCA2mutations. Conclusions: In HGSOC, pts with higher PD-1 level on tumor CD4 and CD8 T cells and higher mutation burden at baseline may have a better outcome following treatment with Pembro. POLE mutation is rare in HGSOC but may correlate with checkpoint inhibitor activity. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS BRCA2 protein CD4 antigen CD8 antigen endogenous compound programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female male ovary cancer EMTREE MEDICAL INDEX TERMS cancer patient clinical trial cohort analysis controlled study DNA RNA hybridization drug therapy drug toxicity fatigue fluorescence gene expression gene frequency gene mutation germ line human human cell human tissue hyponatremia immunohistochemistry immunophenotyping landscape major clinical study myeloid-derived suppressor cell organ culture response evaluation criteria in solid tumors side effect T lymphocyte tumor biopsy tumor regression CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617434862 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 40 TITLE Evaluating the repertoire of immune checkpoint markers expressed on peripheral and ascites CD8+ T cells in ovarian cancer AUTHOR NAMES Gaillard S. Dumbauld C. Bilewski A. Ehrisman J.A. Secord A.A. Havrilesky L.J. Berchuck A. Weinhold K. Chan C. Yi J. AUTHOR ADDRESSES (Gaillard S.; Dumbauld C.; Bilewski A.; Ehrisman J.A.; Secord A.A.; Havrilesky L.J.; Berchuck A.; Weinhold K.; Chan C.; Yi J.) Duke Cancer Institute, Duke University Medical Center, Durham, NC; Duke University Medical Center, Durham, NC; Duke University, Durham, NC; Division of Gynecologic Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, NC CORRESPONDENCE ADDRESS S. Gaillard, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Understanding the immune checkpoint marker repertoire can facilitate development of therapeutic strategies to improve efficacy of immune-based therapies. We used a novel high-dimensional flow cytometry panel to determine co-expression patterns of immune checkpoint markers and effector function of CD8+ T cells from peripheral blood and ascites of patients newly diagnosed with ovarian cancer. Methods: Peripheral blood and ascites samples were collected from patients with epithelial ovarian cancer (n=8). Cells isolated from peripheral blood and ascites were used for immune profiling by multiparameter flow cytometry of 5 inhibitory receptors (PD-1, LAG-3, TIM-3, TIGIT, and BTLA) on CD8+ T cells, along with 4 functional parameters (production of each of the following: TNF-α, IFN-γ, IL-2, and upregulation of CD107a). A complementary multiplex analysis on plasma and ascites fluid was performed to quantify 14 soluble checkpoint markers. Results: The concentrations of soluble PD-1, TIM-3, LAG-3, CTLA-4, BTLA, IDO, and CD137 were increased in ascites fluid compared to plasma from patients with ovarian cancer. Ascites CD8+ T cells co-express higher levels of inhibitory receptors than peripheral CD8+ T cells. In total, CD8+ T cells in ascites retained the ability to produce effector functions at levels similar to peripheral blood. However, IFN-γ production was retained in PD-1 only expressing CD8+ T cells and decreased in CD8+ T cells co-expressing multiple receptors. Conclusions: High-dimensional flow cytometry allowed for the phenotypic and functional characterization of CD8+ T cells from ovarian cancer patients. The profile of receptor co-expression was distinct in peripheral blood compared to ascites. Collectively, our study suggests that co-expression of factors beyond PD-1 influences CD8+ T cell activity. Thus blocking PD-1 and PD-L1 alone may not be sufficient for CD8+ T cells expressing multiple inhibitory receptors. EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 endogenous compound gamma interferon hepatitis A virus cellular receptor 2 interleukin 2 lysosome associated membrane protein 1 programmed death 1 ligand 1 programmed death 1 receptor tumor necrosis factor tumor necrosis factor receptor superfamily member 9 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) ascites fluid CD8+ T lymphocyte female ovary carcinoma EMTREE MEDICAL INDEX TERMS cancer patient cell activity clinical article controlled study diagnosis flow cytometry gene expression gene inactivation human human cell human tissue male plasma quantitative study solubility upregulation CAS REGISTRY NUMBERS gamma interferon (82115-62-6) interleukin 2 (85898-30-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617435507 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 41 TITLE A phase II study of pembrolizumab and docetaxel for aggressive RAI refractory thyroid carcinomas or salivary gland cancers: The iPRIME study AUTHOR NAMES Seiwert T.Y. De Souza J.A. Vokes E.E. Agrawal N. AUTHOR ADDRESSES (Seiwert T.Y.; De Souza J.A.; Vokes E.E.; Agrawal N.) University of Chicago, Chicago, IL; The University of Chicago, Chicago, IL; Johns Hopkins University School of Medicine, Baltimore, MD CORRESPONDENCE ADDRESS T.Y. Seiwert, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Both aggressive, radioactive iodine refractory thyroid cancers as well as high-grade salivary gland cancers respond poorly to chemotherapy, and there is no widely used standard of care. Targeted thearpies as well as cytotoxic chemotherapy (e.g. doxorubicin, or taxanes) are commonly used, but are only modestly effective. Both salivary gland and thyroid cancers have been shown to have tumor inflltrating lymphocytes, tumor inflammation, and PD-L1 expression (Ayers, AACR 2015). Early data with anti-PD-1 immunotherapy using pembrolizumab (Keynote 28) show activity in ≥10a% of patients in a biomarker selected population (Keynote 28 thyroid and salivary gland cohorts). However, most patients are not PD-L1 positive and were not eligible. Recently synergy of anti-PD-1 checkpoint blockade with cytotoxic chemotherapy was reported in several studies (e.g. Langer et al, Keynote 21G). Mechanistically chemotherapy may increase tumor inflammation, and eradicate immusupressive myeloid derived suppressor cells (MDSCs). Data suggest a significant increase in the response rate e. g. in KN21G from 29% to 55%. Furthermore the depths of responses and durability improve, including patients with PD-L1 negative tumors. Methods: We hypothesize that the combination of PD-1 checkpoint blockade and cytotoxic chemotherapy will show synergistic activity in aggressive thyroid cancers and salivary gland cancers. Eligible patients will have radioactive iodine refractory, aggressive thyroid cancer (cohort A, N = 25 pts), or progressive salivary gland cancers (cohort B, N = 25 pts). There will be no PD-L1 or other biomarker selection. Patients must have progressed on prior therapy. Patients will receive docetaxel at a dose of 75mg/m2 Q21 days as well as pembrolizumab 200mg flat-dose Q21 days intravenously. The primary outcome of this study is response rate. The addition of pembrolizumab to chemotherapy will increase the response rate from 20% (H0) to 40% (H1). A simon two-stage design will be used for each cohort (cohorts A and B) with an estimate 81% power in each arm. Patient screening and enrollment are expected to begin mid 2017. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) docetaxel pembrolizumab EMTREE DRUG INDEX TERMS biological marker doxorubicin endogenous compound programmed death 1 ligand 1 programmed death 1 receptor radioactive iodine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) controlled study salivary gland cancer thyroid carcinoma EMTREE MEDICAL INDEX TERMS adverse drug reaction chemotherapy clinical article clinical trial controlled clinical trial drug therapy female gene expression health care quality human immunotherapy inflammation lymphocyte male myeloid-derived suppressor cell phase 2 clinical trial screening side effect CAS REGISTRY NUMBERS docetaxel (114977-28-5) doxorubicin (23214-92-8, 25316-40-9) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617388535 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 42 TITLE A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor AUTHOR NAMES Cho J. Ahn M.-J. Yoo K.H. Lee H. Kim H.K. Heo M.H. Hong J.H. Sun J.-M. Lee S.-H. Ahn J.S. Park K. AUTHOR ADDRESSES (Cho J.; Ahn M.-J.; Yoo K.H.; Lee H.; Kim H.K.; Heo M.H.; Hong J.H.; Sun J.-M.; Lee S.-H.; Ahn J.S.; Park K.) Inha University Hospital, Incheon, Republic of Korea; Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Samsung Medical Center, Seoul, Republic of Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Samsung Medical Center, Seoul, South Korea; Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul, South Korea CORRESPONDENCE ADDRESS J. Cho, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS corticosteroid endogenous compound immunosuppressive agent neutrophil cytoplasmic antibody platinum EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) carcinoma controlled study female male thymoma EMTREE MEDICAL INDEX TERMS adverse drug reaction anemia anorexia antineoplastic activity autoimmune disease cancer epidemiology chemotherapy clinical article clinical trial colitis comparative effectiveness controlled clinical trial drug megadose drug therapy dyspnea fatigue feasibility study follow up hepatitis human myasthenia gravis myocarditis myoclonus pain pharmacokinetics phase 2 clinical trial progression free survival rapidly progressive glomerulonephritis safety side effect systemic therapy thorax wall thyroiditis toxicity tumor growth CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617388467 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 43 TITLE Pembrolizumab in patients (pts) with PD-L1-positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028 AUTHOR NAMES Varga A. Piha-Paul S.A. Ott P.A. Mehnert J.M. Berton-Rigaud D. Morosky A. Zhao G.Q. Rangwala R.A. Matei D. AUTHOR ADDRESSES (Varga A.; Piha-Paul S.A.; Ott P.A.; Mehnert J.M.; Berton-Rigaud D.; Morosky A.; Zhao G.Q.; Rangwala R.A.; Matei D.) Institut Gustave Roussy, Villejuif, France; The University of Texas MD Anderson Cancer Center, Houston, TX; Dana-Farber Cancer Institute, Boston, MA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; ICO Centre René Gauducheau, Saint-Herblain, France; Merck & Co., Inc., Kenilworth, NJ; Merck Research Laboratories, Beijing, China; Northwestern University Feinberg School of Medicine, Chicago, IL View Less CORRESPONDENCE ADDRESS A. Varga, SOURCE Journal of Clinical Oncology (2017) 35:15 Supplement 1. Date of Publication: 20 Jun 2017 CONFERENCE NAME 2017 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2017-06-02 to 2017-06-06 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Overexpression of the PD-1 ligand PD-L1 has been demonstrated in ovarian cancer and may hinder an effective antitumor immune response. A preliminary analysis of the ovarian cancer cohort of the KEYNOTE-028 study (NCT02054806) suggested that the PD-1 inhibitor pembrolizumab has promising antitumor activity in pts with PD-L1 advanced ovarian cancer. An updated analysis of the ovarian cancer cohort based on 15.5 months of follow-up is presented. Methods: Key eligibility criteria for the ovarian cohort of this nonrandomized, multicohort phase Ib trial were advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of prior therapy; PD-L1 positivity defined as membranous staining on ≥1% of tumor and associated inflammatory cells or positive staining in stroma; and ECOG PS 0/1. Pembrolizumab (10 mg/kg every 2 wk) was given for ≤2 y or until confirmed progression/unacceptable toxicity. Response was assessed per RECIST v1.1 by investigators every 8 wk for the first 6 mo and every 12 wk thereafter. Primary end points were safety, tolerability, and confirmed ORR. Results: 26 pts (median age, 57.5 y) were enrolled; 61.5% were white, 38.5% received ≥5 therapies for recurrent/metastatic disease, and 53.8% received prior neoadjuvant/adjuvant therapies. As of the October 10, 2016, data cutoff, the median follow-up duration was 15.5 mo (range, 2.4-30.8 mo). 1 pt had a complete response and 2 had partial responses; 6 pts had stable disease as best response. ORR was 11.5% (95% CI, 2.4%-30.2%). Tumor reduction was observed in 6/26 (23.1%); all 3 patients who responded completed 2 years of treatment. Median duration of response was not reached (range, 24.9+ to 26.5+ mo). Median (95% CI) PFS and OS were 1.9 mo (1.8-3.2 mo) and 13.1 mo (6.7- 17.5 mo) respectively. Treatment-related AEs occurred in 73.1% of pts, and the most common were arthralgia (19.2%), nausea (15.4%), pruritus (15.4%), rash (11.5%), and diarrhea (11.5%). 1 patient had a grade 3 drug-related adverse event (transaminase increased). Conclusions: With 15.5 mo of follow-up, pembrolizumab continued to be well tolerated and demonstrated durable antitumor activity in pts with advanced ovarian cancer. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS aminotransferase endogenous compound EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) ovary cancer EMTREE MEDICAL INDEX TERMS adjuvant chemotherapy adult adverse drug reaction antineoplastic activity arthralgia clinical article controlled clinical trial controlled study diarrhea drug therapy Fallopian tube female follow up human inflammatory cell metastasis middle aged nausea peritoneum cancer phase 1 clinical trial pruritus rash recurrent disease remission response evaluation criteria in solid tumors safety side effect staining stroma toxicity treatment failure CAS REGISTRY NUMBERS aminotransferase (9031-66-7) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617388555 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 44 TITLE Ipilimumab/Nivolumab induced adrenal insufficiency in a patient with metastatic malignant melanoma AUTHOR NAMES Ramadhas A. Subauste J.S. AUTHOR ADDRESSES (Ramadhas A.; Subauste J.S.) University of Mississippi Medical Center, Jackson, United States. CORRESPONDENCE ADDRESS A. Ramadhas, University of Mississippi Medical Center, Jackson, United States. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: The anti-CTLA-4 (anti-cytotoxic T lymphocyte antigen-4) antibody Ipilimumab and the anti-PD-1 antibodies Nivolumab has improved survival in metastatic melanoma. Augmented immune response by the combination treatment carries a risk of adrenal insufficiency. Clinical case: A 64 year old male with metastatic melanoma on Ipilimumab and Nivolumab presented with fever, chills, nausea, vomiting, fatigue, decreased energy, loss of appetite, weight loss of 17 lbs in 5 months. Denied any joint pain or muscle pain or TB or fungal infection in the past. Denied being on steroids in the past, any headache or vision problems or any bleeding disorders or being on any anticoagulants. Admission vitals revealed Hypotension with BP 80/51 with fever of 101F. He was treated for pneumonia with antibiotics but was persistently hypotensive even after IV fluids. Examination significant for very sick looking, thin fragile male but no hyperpigmentation. Labs significant for hyponatremia ( 127mmoL/L, n 135-145 mmoL/L) , normal potassium (3.9 μmol/L, n 3.5-5.1 μmol/L).Baseline morning cortisol (1.1 μg/dL, n am 6.7-22.6μg/dL),ACTH ( 4.2pg/ml, n 7.2-63.3 pg/ml)obtained and meanwhile cosyntropin stimulation test done and cortisol after 30 min and 60 min ( 8.6 μg/dL,14.6 μg/dL ,n>18 μg/dL). Meanwhile stress dose glucocorticoids given (Hydrocortisone 100 mg iv one dose followed by 50 mg iv every 6 hourly).Pituitary panel was done and significant for low testosterone (1.1 ng/mL, n 1.8-7.8 ng/mL) with low normal LH (4.2 mIU/mL, n 1.2-8.6 mIU/mL) and FSH (3.5 mIU/mL, n 1.3-19.3 mIU/mL) suggestive of gonadal axis suppression due to acute stress.TSH was suppressed (TSH-0.01 uIU/mL, n 0.34-5.6 uIU/mL) with normal free T4 (0.92 ng/dL, n 0.61-1.12 ng/dL) and Total T3 (106 ng/dL, n 71-180 ng/dL) suggestive of subclinical thyrotoxicosis related to thyroiditis.MRI pituitary was done which showed 2 mm hypoenhancement in the pituitary suggestive of benign pars intermedia cyst and no abnormal mass or enhancement within the sellar or suprasellar region. He clinically improved with his hypotension and hyponatremia resolved the next day. Fatigue, nausea, vomiting and appetite improved. Hydrocortisone was tapered and patient was discharged on oral hydrocortisone. The lack of hypokalemia and hyperpigmentation and the decreased ACTH level was suggestive of central adrenal insufficiency rather than primary adrenal insufficiency. Conclusion: CTLA-4 inhibitors Ipilimumab and the PD-1 inhibitors Nivolumab have demonstrated clinical efficacy in the management of metastatic malignant melanoma and so all these medications are used in increasing number of patients. Combination treatment can lead to hypophysitis and adrenal insufficiency and the physician must be able to recognize this because often the symptoms are vague and the diagnosis is missed .Prompt diagnosis and management could prevent morbidity and death. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab nivolumab EMTREE DRUG INDEX TERMS antibiotic agent anticoagulant agent antihypertensive agent corticotropin cytotoxic T lymphocyte antigen 4 endogenous compound hydrocortisone potassium programmed death 1 receptor testosterone tetracosactide thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency metastatic melanoma EMTREE MEDICAL INDEX TERMS acute stress Addison disease adult adverse drug reaction arthralgia bleeding body weight loss cancer epidemiology chemical stress chill cyst death diagnosis drug combination drug therapy fatigue fever free thyroxine index gene inactivation gonad headache human hyperpigmentation hypokalemia hyponatremia hypophysis intermediate lobe hypophysitis hypotension liquid loss of appetite major clinical study male middle aged morbidity myalgia mycosis nausea and vomiting nuclear magnetic resonance imaging physician pneumonia provocation test side effect symptom thyroiditis thyrotoxicosis vision CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) nivolumab (946414-94-4) potassium (7440-09-7) testosterone (58-22-0) tetracosactide (16960-16-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151889 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 45 TITLE Nivolumab induced auto-immune diabetes mellitus and thyroiditis: A case report AUTHOR NAMES Reddy S.C. Darapu H. Agarwal M. AUTHOR ADDRESSES (Reddy S.C.) University of Alabama at Birmingham, Birmingham, United States. (Darapu H.) Brookwood Baptist Health, Birmingham, United States. (Agarwal M.) UAB, Birmingham, United States. CORRESPONDENCE ADDRESS S.C. Reddy, University of Alabama at Birmingham, Birmingham, United States. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction Nivolumab is a PD-1 (Programmed cell death) binding immune check point inhibitor that is used to treat various cancers including non-small cell lung cancer (NSCLC). It is associated with immune related adverse events (IRAEs) that can be life threatening. Clinical case A 66 year old white man with stage IV NSCLC was started on Nivolumab due to progressive disease. The thyroid function tests, cortisol and glucose were normal before initiation of Nivolumab. After the second cycle, he presented with one-week history of anorexia and abdominal pain. The evaluation revealed atrial fibrillation with rapid ventricular rate and severe metabolic acidosis due to diabetic ketoacidosis (DKA) with glucose of 700 mg/dl. The C-peptide level was low at < 0.1 ng/mL (0.9 -7.1) with a glucose of 238 mg/dl. The Glutamic Acid Decarboxylase (GAD) antibodies were elevated at 250 IU/mL (< 5). He was managed with insulin infusion, fluid resuscitation and beta blockers. He was later transitioned to basal-bolus insulin regimen. The TSH was suppressed at 0.035 U/ml (0.2-5.5); free T3 4.9 pg/ml (2.3-4.2) and free T4 2.44 ng/dl (0.6-1.5) were elevated. Thyroid gland was not enlarged. The Thyroperoxidase antibody (TPO) were elevated at 273 IU/ml (< 9) but the Thyroid stimulating immunoglobin (TSI) antibodies were not elevated. Thyroid ultrasound showed mildly heterogeneous thyroid gland without nodules. Thyroid uptake and scan could not be completed due to recent exposure to iodinated contrast. Thyrotoxicosis was managed with methimazole and metoprolol. Prednisone was not initiated due to concern for reducing the anti-tumor activity of Nivolumab. Subsequently there was worsening of thyrotoxicosis during outpatient follow up which prompted initiation of prednisone 40 mg/day and methimazole was discontinued. The thyroid function tests normalized within 4 weeks and prednisone was subsequently discontinued. The follow up thyroid function tests remained normal. Thyrotoxicosis and diabetic ketoacidosis/T1DM occurred simultaneously in our patient. Nivolumab was discontinued and patient was started on gemcitabine. Conclusion Nivolumab and other immune check point inhibitors like ipilimumab (cytotoxic T-lymphocyte associated antigen 4 [CTLA-4] inhibitor) enhance antitumor activity by blocking negative regulators of T-cell function in both tumor cells and immune cells which causes autoimmune systemic diseases. There should be high index of suspicion for autoimmune dysfunction when evaluating these patients with nonspecific symptoms and routine surveillance for endocrine dysfunction should be considered. Early recognition and prompt treatment of IRAEs can be life-saving. Anti PD-1 inhibitors are associated higher incidence of thyroid disease compared to CTLA-4 inhibitors. The IRAEs are primarily managed by immunosuppression with corticosteroids and discontinuation of immunotherapy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS C peptide cytotoxic T lymphocyte antigen 4 endogenous compound gemcitabine glucose glutamate decarboxylase antibody hydrocortisone immunoglobulin insulin ipilimumab metoprolol prednisone programmed death 1 receptor thiamazole thrombopoietin thyroid peroxidase thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) diabetic ketoacidosis thyroiditis EMTREE MEDICAL INDEX TERMS abdominal pain adverse drug reaction aged anorexia antineoplastic activity atrial fibrillation case report cell function drug therapy exposure fluid resuscitation follow up free liothyronine index free thyroxine index gene inactivation human immunocompetent cell immunosuppressive treatment insulin dependent diabetes mellitus insulin infusion iodination male metabolic acidosis non small cell lung cancer outpatient side effect symptom systemic disease T lymphocyte thyroid disease thyroid function test thyrotoxicosis tumor cell ultrasound CAS REGISTRY NUMBERS C peptide (59112-80-0) gemcitabine (103882-84-4) glucose (50-99-7, 84778-64-3) hydrocortisone (50-23-7) immunoglobulin (9007-83-4) insulin (9004-10-8) ipilimumab (477202-00-9) metoprolol (37350-58-6) nivolumab (946414-94-4) prednisone (53-03-2) thiamazole (60-56-0) thrombopoietin (9014-42-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151303 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 46 TITLE Calcitonin response following sequential use of a yeast-CEA therapeutic cancer vaccine and avelumab, a monoclonal anti-PD-LI inhibitor, in metastatic medullary thyroid cancer AUTHOR NAMES Del Rivero J. Bilusic M. Rauckhorsts M. Cordes L. Karsai F. Strauss J. Dahut W.L. Schlom J. Gulley J.L. Madan R.A. AUTHOR ADDRESSES (Del Rivero J.; Bilusic M.; Rauckhorsts M.; Cordes L.; Karsai F.; Strauss J.; Dahut W.L.; Schlom J.; Gulley J.L.; Madan R.A.) National Cancer Institute, National Institutes of Health, Bethesda, United States. CORRESPONDENCE ADDRESS J. Del Rivero, National Cancer Institute, National Institutes of Health, Bethesda, United States. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Medullary thyroid cancer (MTC) accounts for approximately 4% of thyroid carcinomas, and secretes calcitonin and carcinoembryonic antigen (CEA). Patients with unresectable, metastatic disease are candidates for approved agents with either vandetanib and cabozantinib, but toxicity limits their use. There are ongoing trials exploring the role of less toxic immunotherapy in patients with MTC. Patient findings: A 61-year-old male presented with an enlarging anterior neck mass, fine needle aspiration was consistent with MTC. He underwent total thyroidectomy with bilateral neck dissection. Subsequently, he had multiple local recurrences and has had a total of five neck surgeries in a period of 12 years. Based on the elevated calcitonin levels and persistent local recurrence, 13 years after diagnosis, he started systemic treatment with sunitinib and calcitonin levels nadired to 199 pg/ml (n<10) down from 461 pg/ml. He continued for 5 years and stopped due to side effects. His calcitonin levels after discontinuing sunitinib rose to 2243 pg/ml. He presented to the National Cancer Institute and enrolled on a clinical trial with yeast-based therapeutic cancer vaccine targeting CEA (NCT01856920). During 6-month protocol mandated surveillance he had calcitonin doubling time of 135 days. During the subsequent 3 month vaccine period his doubling time improved to 530 days. He decided to come off study electively for surgical removal of his largest neck lymph node. After surgery, his calcitonin rose to 9765 pg/ml and the patient was enrolled on a phase 1 trial of avelumab, a PD-L1 inhibitor (NCT01772004). He then had 5 consecutive declines in his calcitonin to 5732 pg/ml while on the immune checkpoint inhibitor, a greater than 40% decline not previously seen in his NCI clinical course. These findings coincided with an immune-related adverse event (asymptomatic rise in grade 3 lipase) which led to protocol-mandated treatment discontinuation. A subsequent analysis of the patient's lymph node resected post vaccination revealed tumor that was PD-L1 positive. Conclusion: Here we present a case with recurrent MTC who was treated initially with sunitinib, and then subsequently enrolled on a clinical trial with yeast-CEA vaccine. After a surgical resection, the tumor sample resected demonstrated positive PD-L1 expression. The patient had a 40% decline in serologic markers on an anti- PD-L1 therapy (avelumab). Emerging data suggest that immune cells mobilized to the tumor via immunotherapy (vaccine) could enhance PD-L1 expression, although the absence of baseline tissue prevents confirmation in this case. This case highlights the potential for immunotherapy or sequential immunotherapy in MTC. A trial will open at the NCI treating patients (both with previous immunotherapy and immunotherapy naive) with an immune checkpoint inhibitor. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab calcitonin cancer vaccine EMTREE DRUG INDEX TERMS carcinoembryonic antigen endogenous compound programmed death 1 ligand 1 sunitinib triacylglycerol lipase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) nonhuman thyroid medullary carcinoma yeast EMTREE MEDICAL INDEX TERMS adult adverse drug reaction cervical lymph node clinical article clinical trial controlled clinical trial controlled study diagnosis disease duration drug therapy drug withdrawal fine needle aspiration biopsy gene expression gene inactivation human human tissue immunocompetent cell immunotherapy male middle aged national health organization neck dissection neck tumor phase 1 clinical trial relapse side effect surgery systemic therapy thyroidectomy vaccination CAS REGISTRY NUMBERS avelumab (1537032-82-8) calcitonin (12321-44-7, 21215-62-3, 9007-12-9) sunitinib (341031-54-7, 557795-19-4) triacylglycerol lipase (9001-62-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151209 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 47 TITLE The retrospective single center study of nivolumab induced thyroid dysfunction in malignant melanoma AUTHOR NAMES Yano S. Ashida K. Terada E. Tadakuma H. Takeichi Y. Hanada Y. Nagata H. Sakamoto S. Nomura M. Ogawa Y. AUTHOR ADDRESSES (Yano S.; Ashida K.; Terada E.; Tadakuma H.; Takeichi Y.; Hanada Y.; Nagata H.; Sakamoto S.; Nomura M.; Ogawa Y.) Kyushu University Hospital, Japan. CORRESPONDENCE ADDRESS S. Yano, Kyushu University Hospital, Japan. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Context: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved survival in malignant melanoma. In spite of its efficacy, it frequently induces immune related adverse events (irAEs) such as thyroid dysfunction. The character of thyroid related AE remains to be fully understood. Objective: To evaluate and characterize the nivolumab induced thyroid dysfunction. Design and settings: We analyzed retrospectively 36 malignant melanoma patients (aged 17-85 years; 65% females), who underwent nivolumab therapy at Kyushu University Hospital between September 1st, 2014 and September 30th, 2016. There were 11 excluded patients, consisting of 7 patients without estimated thyroid function and 4 patients with history of thyroid function disorder. Main Outcome Measures: Patient characteristics, administration period, thyroid function [thyroid-stimulating hormone (TSH), free thyroxine (free T4) and free triiodothyronine (fT3)], and anti-thyroid antibodies (ATA) such as anti-thyroglobulin antibody and anti-thyroid peroxidase antibody were observed. Results: Adverse events of thyroid dysfunction were observed in 8 patients (8/25; 32%). 4 cases of them showed thyrotoxicosis, and 3 turned to hypothyroidism sequentially. The other remained 4 cases showed isolated hypothyroidism. Levothyroxine replacement was required in 3 of 7 hypothyroid patients. Anti-thyroglobulin antibody was elevated in 1 of 5 available patients with thyroid related AE, while it was elevated in 1 of 19 patients without thyroid related AE. Anti-thyroid peroxidase antibody was negative in all patients. The administration period was longer in patients with thyroid related AE than in patients without thyroid related AE (p<0.01). There was no significant difference between groups with/without thyroid related AE for age, gender, tumor stage, response to the most recent therapy, thyroid function, and ATA. Conclusion: Thyroid dysfunction was common adverse event of nivolumab in malignant melanoma. Because ATA had not predicted the nivolumab induced thyroid dysfunction, ATA-independent thyroid related AE could be induced. Further studies are needed to clarify the characters and predicting factors of thyroid related AE. Regular monitoring and awareness of thyroid dysfunction are recommended, especially in patients who received nivolumab therapy for long term. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS antithyroid agent endogenous compound levothyroxine liothyronine peroxidase thyroglobulin antibody thyroid antibody thyrotropin thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) melanoma thyrotoxicosis EMTREE MEDICAL INDEX TERMS adolescent adverse drug reaction awareness cancer staging clinical article clinical trial controlled study drug therapy female free thyroxine index gender human hypothyroidism male monitoring side effect thyroid function university hospital CAS REGISTRY NUMBERS levothyroxine (51-48-9) liothyronine (6138-47-2, 6893-02-3) nivolumab (946414-94-4) peroxidase (9003-99-0) thyrotropin (9002-71-5) thyroxine (7488-70-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151011 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 48 TITLE Incidence of thyroid adverse events in patients with non-small-cell lung cancer (NSCLC) during nivolumab treatment AUTHOR NAMES Campredon P. Bigay-Game L. Mouly C. Bousquet E. Mazières J. Caron P. AUTHOR ADDRESSES (Campredon P.; Bigay-Game L.; Mouly C.; Bousquet E.; Mazières J.; Caron P.) CHU Larrey, Toulouse, France. CORRESPONDENCE ADDRESS P. Caron, CHU Larrey, Toulouse, France. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: Immunotherapy with nivolumab, an anti-programmed cell death 1 receptor (PD-1) monoclonal antibody, is becoming a standard of care for many cancers including NSCLC. Among endocrine-related adverse events, thyroid disorders are frequently observed but no clear recommendations have been proposed so far. Objective: To assess the incidence of thyroid adverse events in patients with NSCLC during nivolumab treatment. Patients and Methods: Retrospective study on patients with NSCLC treated with nivolumab between May 2015 and August 2016. Patients with normal TSH level in the 3 months before the beginning of immunotherapy and receiving at least 2 infusions of nivolumab were included. Patients treated with levothyroxine, amiodarone, or another immunotherapy simultaneously were excluded. Clinical and hormonal follow-up was performed until the end of immunotherapy, patient death or October 2016. Results: 156 patients with NSCLC received at least one infusion of nivolumab. 92 patients were included (62 men, median age: 61.8 years). Thirteen (14.1%) thyroid dysfunctions were diagnosed: patients were more frequent female (61.5% versus 27.8%, p=0.02) and younger (57.3 versus 62.5 years, p=0.03) than in the group without thyroid dysfunction. Thyrotoxicosis was observed in 11 patients (TSH= 0.05 mU/L, fT4= 25.4 pg/ml, fT3= 5.0 pg/ml) after a median of 3 infusions, and 4 patients displayed secondary hypothyroidism after a median of 4 infusions, suggesting a biphasic thyroiditis. Anti-TPO antibodies were present in 2 of 9 evaluated patients (15.3%). Primary hypothyroidism (n=2) appeared after a median of 15 infusions. Six patients received specific treatment for thyroid dysfunctions (corticosteroids n=3, anti-thyroid drugs n=1 and/or levothyroxine n=6) and 3 patients stopped transiently immunotherapy due to thyroid dysfunctions. Conclusion: Thyroid dysfunctions are frequent during nivolumab treatment of patients with NSCLC. Isolated thyrotoxicosis and biphasic thyroiditis are the most frequent thyroid-related adverse events. Prospective studies are necessary to determine the mechanism(s) of thyroid dysfunctions during nivolumab treatment. In clinical practice, serum TSH levels should be regularly evaluated during nivolumab treatment of patients with NSCLC. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS amiodarone antithyroid agent endogenous compound levothyroxine thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) non small cell lung cancer side effect EMTREE MEDICAL INDEX TERMS adult adverse drug reaction clinical practice clinical trial death diagnosis drug therapy female follow up gene expression human human tissue hypothyroidism immunotherapy infusion major clinical study male middle aged prospective study retrospective study thyroiditis thyrotoxicosis thyrotropin blood level CAS REGISTRY NUMBERS amiodarone (1951-25-3, 19774-82-4, 62067-87-2) levothyroxine (51-48-9) nivolumab (946414-94-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151581 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 49 TITLE Nivolumab induced autoimmune diabetes in a patient with metastatic renal cell carcinoma: A case report AUTHOR NAMES Vodopivec D.M. Piech M.R. Tretter C.G. AUTHOR ADDRESSES (Vodopivec D.M.; Piech M.R.; Tretter C.G.) Lahey Hospital, Medical Center, Burlington, United States. CORRESPONDENCE ADDRESS D.M. Vodopivec, Lahey Hospital, Medical Center, Burlington, United States. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: We report a case of hyperosmolar hyperglycemic state (HHS) as the initial presentation of newly diagnosed autoimmune insulin-dependent diabetes mellitus (DM) in a patient with metastatic clear cell renal cell carcinoma (MCCRCC) receiving nivolumab (anti-PD-1 monoclonal antibody) immunotherapy. Clinical case: 78 yo man with no personal history of DM and no evidence of pancreatic metastasis was started on nivolumab (3 mg/kg, once every 2 weeks) for MCCRCC to the lung and left tibia. Four months after starting immunotherapy, he presented with fatigue, polyuria, polydipsia and blurring of vision for several days. The patient denied nausea, vomiting, abdominal pain, fever, urinary symptoms, chest pain, or steroid use. Physical exam revealed a confused, chronic-ill appearing man with some recent weight loss, hypotension with no tachycardia (on metoprolol), dry mucous membranes and decreased skin turgor; all concerning signs for moderate to severe dehydration. Laboratory studies were significant for normal leukocyte count without bandemia, hyperglycemia (810 mg/dL, n70-100 mg/dL), hyponatremia (116 mEq/L, n135-146 mEq/L), hyperkalemia (5.4 mEq/L, n3.4-5.2 mEq/L), hypochloremia (80 mEq/L, n98-110mEq/L), normal bicarbonate (25 mmol/L, n24-32 mmol/L), elevated BUN (38 mg/dL, n8-24 mg/dL), elevated creatinine (1.8 mg/dL, n0.6-1.3 mg/dL). Serum osmolality was elevated (311 mOsm/kg, n280-295 mOsm/kg) with normal serum anion gap and negative serum acetone. C-peptide was in the normal range after initiation of insulin drip (1.6 ng/mL, n0.8-3.5 ng/mL). He had positive GAD antibody (50.1 lU/mL, n0.0-5.0 lU/mL) with negative insulin and islet cell antibodies. HbA1c was elevated (9.2 %, n4.6%-5.6%) with glycosuria but without ketonuria. CXR did not show acute consolidation and EKG was negative for ischemic changes. A diagnosis of HHS was made as a complication of nivolumab induced autoimmune DM. The patient was given IV fluids, electrolyte repletion, and started on insulin drip. Once his clinical status stabilized, he was switched to SC basal bolus insulin regimen and discharged home. It is important to highlight that HbA1 C was 5.3% prior to initiation of nivolumab. Random blood glucose values were normal until 2 months after initiation of immunotherapy when frank hyperglycemia developed with blood glucose over 200 mg/dL. Conclusion: Anti PD-1 immunotherapy targets T-cell regulation. This is effective in tumor cell death in multiple malignancies, but has also been associated with endocrine immune related adverse events. Once diagnosed, autoimmune diabetes is a treatable disease, but its rapid presentation with acute metabolic complication is important to recognize due to potential morbidity and mortality. Physicians must be aware of this adverse event and establish routine measurement of both blood glucose levels and HbA1 c when administering anti PD-1 immunotherapy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS acetone bicarbonate C peptide creatinine electrolyte endogenous compound hemoglobin A1c insulin metoprolol pancreas islet cell antibody programmed death 1 receptor steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) insulin dependent diabetes mellitus kidney metastasis EMTREE MEDICAL INDEX TERMS abdominal pain anion gap body weight loss cell death dehydration diagnosis drug therapy electrocardiogram endocrine system fatigue fever glucosuria human human tissue hyperglycemia hyperkalemia hypochloremia hyponatremia hypotension immunotherapy ketonuria leukocyte count lung major clinical study male morbidity mortality mucosal dryness nausea and vomiting pancreas metastasis physician polydipsia polyuria serum osmolality skin turgor T lymphocyte tachycardia thorax pain tibia tumor cell vision CAS REGISTRY NUMBERS acetone (67-64-1) bicarbonate (144-55-8, 71-52-3) C peptide (59112-80-0) creatinine (19230-81-0, 60-27-5) hemoglobin A1c (62572-11-6) insulin (9004-10-8) metoprolol (37350-58-6) nivolumab (946414-94-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617155480 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 50 TITLE The incidence and pattern of thyroid dysfunction in lung cancer patients treated with immune checkpoint inhibitors AUTHOR NAMES Lee H. Shin S. Kim H.R. Shin D.Y. Kang E.S. Lee E.J. AUTHOR ADDRESSES (Lee H.; Shin S.) Department of Internal Medicine, Severance Hospital, Yonsei University, South Korea. (Kim H.R.) Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, South Korea. (Shin D.Y.; Kang E.S.; Lee E.J.) Yonsei University, College of Medicine, Seoul, South Korea. CORRESPONDENCE ADDRESS H. Lee, Department of Internal Medicine, Severance Hospital, Yonsei University, South Korea. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background Immunotherapy is an emerging treatment modality in advanced lung cancer as well as other solid tumors. However, immune-related adverse reactions (irAE) are frequent toxicities that often cause limitation in treatment, and may sometimes become life-threatening. Thyroid dysfunction is common during treatment with immune checkpoint inhibitors, but its characteristics and clinical course has yet to be elucidated. We assessed the patterns and characteristics of immune-related thyroid dysfunction in lung cancer patients treated with pembrolizumab, atezolizumab, and nivolumab. Methods One hundred and twenty-three patients with advanced lung cancer who received either pembrolizumab, atezolizumab, or nivolumab were reviewed. Baseline and routine follow-up thyroid function tests were done throughout the treatment. Results Eighteen patients (14.6%) showed overt or subclinical thyroid dysfunction during immune checkpoint blockade. Median age was 67.0 years (range, 42.0-87.5) in thyroid irAE, and 62.9 years (range, 25.4-84.6) in euthyroid patients (p=0.9). Females were 33.3% and 26.7% in thyroid irAE and euthyroid patients, respectively (p=0.6). Thyroid dysfunction occurred in 5 out of 29 patients (17.2%), 2 out of 17 patients (11.8%), 11 out of 77 patients (14.3%) treated with pembrolizumab, atezolizumab, and nivolumab, respectively. Among all patients treated with immune checkpoint inhibitors, 11 patients (8.9%) experienced hyperthyroidism, of which 2 patients subsequently developed hypothyroidism. The median onset of hyperthyroidism was 4.4 weeks (range, 1.9-18.0). Four patients developed overt thyrotoxicosis with peak free T4 level of 2.83 ± 2.15 ng/dL. Seven patients (5.7%) showed isolated hypothyroidism without preceding thyrotoxicosis. The peak level of TSH was 40.21 ± 41.98 μIU/mL, and the median onset of isolated hypothyroidism was 9 weeks (range, 3.1-26.7) after the first treatment. Elevated thyroid autoantibodies were documented in 3 patients. 7 out of 9 hypothyroid patients received levothyroxine replacement. Conclusions Immune-related thyroid dysfunction is common during immune checkpoint blockade in lung cancer. Baseline demographics including age and sex was not statistically different between euthyroid patients and those developing thyroid dysfunction. Pembrolizumab, atezolizumab, and nivolumab showed similar incidence of thyroid irAE. Further investigation of risk factors and predictive markers associated with immune-related thyroid dysfunction would be of great interest. EMTREE DRUG INDEX TERMS atezolizumab endogenous compound levothyroxine nivolumab pembrolizumab thyroid antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer patient lung cancer thyrotoxicosis EMTREE MEDICAL INDEX TERMS adult adverse drug reaction aged clinical trial drug combination drug therapy female follow up free thyroxine index gene expression human hypothyroidism major clinical study risk factor side effect thyroid function test CAS REGISTRY NUMBERS atezolizumab (1380723-44-3) levothyroxine (51-48-9) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151687 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 51 TITLE A case of acute severe insulin resistance and fulminant type 1 diabetes after immune checkpoint blockade cancer therapy AUTHOR NAMES Lee J.Y.M. Warshauer J.T. Gilliam L.K. Park-Sigal J. Murphy E.J. Anderson M.S. AUTHOR ADDRESSES (Lee J.Y.M.; Warshauer J.T.; Park-Sigal J.; Murphy E.J.; Anderson M.S.) University of California, San Francisco, San Francisco, United States. (Gilliam L.K.) Kaiser Permanente, South San Francisco Medical Center, South San Francisco, United States. CORRESPONDENCE ADDRESS J.Y.M. Lee, University of California, San Francisco, San Francisco, United States. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Immune checkpoint inhibitors are promising therapies for unresectable metastatic melanoma and other cancers (1). Anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) checkpoint inhibitors are being approved for a growing number of malignancies, and with this rise in use, resultant autoimmune endocrinopathies such as thyroid dysfunction, hypophysitis, adrenalitis, and type 1 diabetes have also emerged (2,3). We describe a case of severely insulin resistant autoimmune diabetes following recent treatment of metastatic melanoma with the PD-1 checkpoint inhibitor pembrolizumab. Clinical Case: An 84 yr old man with impaired glucose tolerance on metformin (HbA1 c 5.7% 4 days prior to admission) and stage 4 melanoma on pembrolizumab (2 mg/kg given 1 month and 4 days prior to admission) was admitted with altered mental status. His initial labs of blood glucose (BG) 1076 mg/dl, pH 6.8, phydroxybutyrate 4.92 mM (nl <0.28), Cr 2.12 mg/dL (nl 0.7-1.30) revealed DKA and acute kidney injury. He was resuscitated aggressively with intravenous (IV) fluids and insulin infusion per DKA protocol. However, he remained extremely hyperglycemic (BG 800-900 mg/dL) requiring upward titration of the insulin to 800 units/h. Given concerns that he had type B insulin resistance due to pembrolizumab, he was given IV methylprednisolone 1g 12h after admission and on hospital day (HD) 2, followed by dexamethasone 40mg on HD 3. After the first dose of methylprednisolone, his BG levels dropped precipitously and continued to fall after discontinuation of his insulin infusion (total 5,500 units in first 24h), necessitating 20% dextrose infusion for > 24h to maintain euglycemia. He had positive GAD65 antibodies at 115 IU/mL (nl 0-5.0) and negative ZnT8 and IA-2 antibodies. C-peptide levels were low at 0.1 ng/mL with BGs >200 mg/dL. He was gradually tapered off steroids and transitioned to a subcutaneous insulin regimen. When he was discharged on HD 11, he required only 20 units of insulin/day with BGs 100-200 mg/dL. C-peptide level was <0.5 ng/mL with BG 113 mg/dL 6 weeks after presentation. The patient was ultimately diagnosed with fulminant type 1 diabetes, as well as type B (autoimmune) insulin resistance, attributed to suspected antibodies to the insulin receptor (to be measured), with no further pembrolizumab treatment planned. Conclusions: This is the first case of type B (autoimmune) insulin resistance in combination with fulminant autoimmune beta-cell destruction associated with pembrolizumab, an immune checkpoint inhibitor. The patient responded to high dose glucocorticoids, although plasmapheresis, cyclophosphamide, and rituximab were also considered (4). Immunologic studies will need to be undertaken to understand how immunotherapy induces autoimmune endocrinopathies in certain individuals and to better elucidate risk factors for this potentially fatal complication. EMTREE DRUG INDEX TERMS C peptide cyclophosphamide dexamethasone endogenous compound glucose glutamate decarboxylase 65 antibody hemoglobin A1c insulin insulin receptor metformin methylprednisolone pembrolizumab programmed death 1 receptor rituximab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer therapy insulin dependent diabetes mellitus insulin resistance EMTREE MEDICAL INDEX TERMS acute kidney failure adverse drug reaction aged case report cell destruction clinical trial diagnosis drug fatality drug megadose drug resistance drug therapy drug withdrawal glucose infusion glucose intolerance hospital human hyperglycemia immunotherapy insulin infusion liquid low drug dose male mental health metastatic melanoma pancreas islet beta cell plasmapheresis risk factor side effect titrimetry very elderly CAS REGISTRY NUMBERS C peptide (59112-80-0) cyclophosphamide (50-18-0) dexamethasone (50-02-2) glucose (50-99-7, 84778-64-3) hemoglobin A1c (62572-11-6) insulin (9004-10-8) metformin (1115-70-4, 657-24-9) methylprednisolone (6923-42-8, 83-43-2) pembrolizumab (1374853-91-4) rituximab (174722-31-7) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617155477 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 52 TITLE Primary hypoparathyroidism: A new endocrine immune related adverse event (irAEs) secondary to combination treatment with PD-1 and CTLA-4 checkpoint inhibitors AUTHOR NAMES Cubb T. Patel S. Tajuddin N. Goodale T. Rodgers T. Trinh V.A. Tawbi H. Dadu R. AUTHOR ADDRESSES (Cubb T.; Tajuddin N.) Baylor College of Medicine, Houston, United States. (Patel S.; Rodgers T.; Trinh V.A.; Tawbi H.; Dadu R.) Houston Methodist Hospital, Houston, United States. (Goodale T.) University of Texas MD Anderson Cancer Center, Houston, United States. CORRESPONDENCE ADDRESS T. Cubb, Baylor College of Medicine, Houston, United States. SOURCE Endocrine Reviews (2017) 38:3 Supplement 1. Date of Publication: 1 Jun 2017 CONFERENCE NAME 99th Annual Meeting of the Endocrine Society, ENDO 2017 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2017-04-01 to 2017-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Context: The advent of checkpoint inhibitors has dramatically impacted the clinical course of multiple malignancies, but these drugs can also result in aberrant immune activation leading to undesirable offtarget inflammation and autoimmunity. Although several endocrine irAEs following administration of anti PD-1 and CTLA-4 agents have been observed, parathyroid involvement has not yet been reported. Case Description: A 73yo male was diagnosed with melanoma for which he underwent surgical excision but a year later developed diffuse metastatic disease involving soft tissue sites, bone, and liver. Combination immunotherapy with Nivolumab (anti PD-1 antibody) and Ipilimumab (anti CTLA-4 antibody) was initiated. Patient underwent two cycles of therapy, but shortly thereafter developed fatigue and bilateral extremity paresthesia. He reported to ED due to progressive symptoms including ataxia requiring use of wheelchair, slow speech, and perioral tingling. On exam, he displayed normal orientation, ataxia, and negative Chvostek/Trousseau sign. Laboratories revealed: total calcium markedly low (5mg/dl, 8.4- 10.2mg/dl), albumin normal (4.1g/dL, 3.5-4.7g/dL), ionized calcium decreased (0.67mMol/L, 1.13- 1.32mMol/L), magnesium low (1.5mg/dL, 1.8-2.9mg/dL), high phosphorous (6.6mg/dL, 2.5-4.5mg/dL), undetectable iPTH (<1.0pg/mL, 9-80pg/mL), decreased 25-hydroxyvitamin D (18ng/mL, 30-100ng/mL), normal 1,25-dihydroxyvitamin D (29pg/mL, 18-64pg/mL), FeCa 0.017, and negative PTH antibody. Evaluation of calcium sensing receptor antibodies was unavailable clinically, but pursued in research setting (pending). Laboratories a week prior to presentation were normal. He had no history of neck radiation and imaging showed no parathyroid infiltrative process. He was admitted with diagnosis of autoimmune primary hypoparathyroidism and started on calcium gluconate drip in addition to oral calcium carbonate, calcitriol, ergocalciferol, and magnesium supplementation. Close laboratory monitoring and aggressive repletion were pursued. He experienced significant improvement in symptoms that correlated with calcium correction. His parathyroid function has not recovered since diagnosis. Other irAEs have included: thyroiditis, hepatitis, dermatitis, and possible neuropathy. IrAEs have been medically managed, and he has shown great response to ongoing therapy. Conclusion: Temporal proximity of hypoparathyroidism to initiation of Ipilimumab and Nivolumab without other mechanism for acute injury points towards immunotherapy as the most likely cause of primary hypoparathyroidism. The underlying etiology is likely nonspecific immune activation, but presence of CaSR antibodies is being evaluated. This case highlights the need to further understand the mechanism of irAEs and increase clinical vigilance to detect early signs and symptoms of endocrine irAEs. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) cytotoxic T lymphocyte antigen 4 programmed death 1 receptor EMTREE DRUG INDEX TERMS 25 hydroxyvitamin D albumin calcitriol calcium calcium carbonate calcium sensing receptor cytotoxic T lymphocyte antigen 4 antibody endogenous compound ergocalciferol gluconate calcium ipilimumab magnesium nivolumab phosphorus EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypoparathyroidism EMTREE MEDICAL INDEX TERMS alertness ataxia bone case report dermatitis diagnosis drug therapy excision fatigue hepatitis human imaging immunotherapy injury limb male melanoma metastasis monitoring neck neuropathy parathyroid function paresthesia radiation soft tissue speech symptom thyroiditis wheelchair CAS REGISTRY NUMBERS 25 hydroxyvitamin D (64719-49-9) calcitriol (32222-06-3, 32511-63-0, 66772-14-3) calcium (7440-70-2, 14092-94-5) calcium carbonate (13397-26-7, 13701-58-1, 14791-73-2, 471-34-1) ergocalciferol (50-14-6, 50809-47-7, 8042-78-2) gluconate calcium (299-28-5) ipilimumab (477202-00-9) magnesium (7439-95-4) nivolumab (946414-94-4) phosphorus (7723-14-0) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L617151660 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 53 TITLE Autoimmune diabetes linked to nivolumab AUTHOR NAMES Nieves C.A. Harlan D.M. Thompson M. Suzuki S. Ali A. AUTHOR ADDRESSES (Nieves C.A.; Harlan D.M.; Thompson M.; Suzuki S.; Ali A.) Worcester, MA, Boston, MA CORRESPONDENCE ADDRESS C.A. Nieves, SOURCE Diabetes (2017) 66 Supplement 1 (A353). Date of Publication: 1 Jun 2017 CONFERENCE NAME 77th Scientific Sessions of the American Diabetes Association, ADA 2017 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2017-06-09 to 2017-06-13 ISSN 1939-327X BOOK PUBLISHER American Diabetes Association Inc. ABSTRACT Background: Nivolumab, an IgG4 monoclonal antibody to programmed death receptor 1 (PD-1) has been associated with autoimmune diabetes. A 75 year old female with history of non-small cell lung cancer received nivolumab for progressive, metastatic disease despite first line chemotherapy. She had a history of prediabetes and her daughter developed autoimmune diabetes at age 55 years. Following her 2nd cycle of nivolumab, she developed mild nausea and occasional episodes of vomiting. She developed polyuria, polydypsia and nocturia two days prior to receiving her 3rd cycle of nivolumab. While receiving her third cycle of nivolumab, she was found to have an elevated blood glucose of 560 mg/dl without anion gap metabolic acidosis. At that time, hemoglobin A1c was 6.7%. Further evaluation revealed positive glutamic acid decarboxylase (17.4 U/mL; <1) and islet cell (10 U; <5) autoantibodies. C-peptide was 3.32 ng/mL with corresponding blood glucose of 456 mg/dl. Insulin therapy was started given suspicion for autoimmune diabetes. The 4th cycle of nivolumab was held for two weeks and subsequently restarted when her glycemic control improved. C-peptide was undetectable (<0.01 ng/mL), three months after her initial diabetes diagnosis, with a corresponding blood glucose of 299 mg/dl. She has since completed 22 cycles of nivolumab and her glycemic control has improved, on multiple daily insulin injection therapy. This case demonstrates early detection and progression towards autoimmune diabetes linked to nivolumab. Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits PD-1 activity. This releases PD-1 pathway-mediated inhibition of the immune response, including reaction to self-antigen and autoimmune diabetes in addition to antitumor response. Although autoimmune diabetes is relatively rare in adults, early suspicion should arise in adults receiving immune therapies for cancer. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS autoantibody C peptide endogenous compound glutamate decarboxylase 67 hemoglobin A1c immunoglobulin G4 programmed death 1 receptor recombinant human insulin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) impaired glucose tolerance EMTREE MEDICAL INDEX TERMS adult aged case report chemotherapy diagnosis drug combination drug therapy female gene inactivation glucose blood level glycemic control human immune response immunotherapy insulin treatment metabolic acidosis metastasis middle aged nausea nocturia non small cell lung cancer pancreas islet cell polydipsia polyuria vomiting CAS REGISTRY NUMBERS C peptide (59112-80-0) hemoglobin A1c (62572-11-6) nivolumab (946414-94-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616961952 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 54 TITLE Phase i study combining PARP-inhibition with immune checkpoint blockade in women with BRCA-deficient recurrent ovarian cancer AUTHOR NAMES Adams S.F. Rixe O. McCance D. Lee J.H. Eberhardt S. Westgate S. Rutledge T. Muller C. AUTHOR ADDRESSES (Adams S.F.; Rutledge T.; Muller C.) University of New Mexico, Albuquerque, United States. (Rixe O.; McCance D.; Lee J.H.; Eberhardt S.; Westgate S.) University of New Mexico Cancer Center, Albuquerque, United States. CORRESPONDENCE ADDRESS S.F. Adams, University of New Mexico, Albuquerque, United States. SOURCE Gynecologic Oncology (2017) 145 Supplement 1 (99-100). Date of Publication: 1 Jun 2017 CONFERENCE NAME 48th Annual Meeting on Women's Cancer of the Society of Gynecologic Oncology, SGO 2017 CONFERENCE LOCATION National Harbor, MD, United States CONFERENCE DATE 2017-03-12 to 2017-03-15 ISSN 1095-6859 BOOK PUBLISHER Academic Press Inc. ABSTRACT Objectives: Preclinical data demonstrate a synergistic therapeutic benefit in BRCA1 ovarian cancer when poly adenosine diphosphateribose polymerase (PARP) inhibition is combined with immune checkpoint blockade. Based on this, a phase I study was conducted to assess the tolerability of this regimen in women with BRCA mutation-associated recurrent ovarian cancer. Method: Eligibility criteria included a documented BRCA1 or BRCA2 germline mutation and a diagnosis of recurrent ovarian, tubal, or primary peritoneal cancer with measurable disease. Both platinum- sensitive and platinum-resistant patients were eligible. Exclusion criteria included current use of antiinflammatory agents or a prior history of autoimmune disease. Treatment consisted of an oral PARPinhibitor at 300 mg twice daily, as well as monthly infusions of the anti-CTLA-4 antibody at a dose of 10 mg/kg, with plans for a dose reduction if toxicity was encountered. Patients completing 2 full treatment cycles were evaluated for evidence of toxicity, particularly immune-related adverse events, to define a dose for phase II testing. Results: Three women were treated at the starting dose of 300 mg BID of the PARP-inhibitor and 10 mg/kg monthly of anti-CTLA-4 antibody for 2 cycleswithout evidence of any dose-limiting toxicities. All patients experienced grade 1 and 2 toxicities consistent with prior studies using immune checkpoint inhibitors. The only grade 3 toxicity was a headache reported by 1 patient, which resolved within 24 hours. All 3 patients showed evidence of treatment response by cycle 3 based on CA125 levels and a decrease in tumor size on CT scans. Conclusion: The combination of PARP-inhibition and CTLA-4 blockade is tolerable in heavily pretreated women with recurrent BRCAassociated ovarian cancer. Preliminary results also demonstrate evidence of therapeutic effect, supporting ongoing evaluation of this regimen in phase II trials. EMTREE DRUG INDEX TERMS antiinflammatory agent BRCA1 protein BRCA2 protein CA 125 antigen cytotoxic T lymphocyte antigen 4 cytotoxic T lymphocyte antigen 4 antibody endogenous compound nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor platinum EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) controlled study ovary cancer EMTREE MEDICAL INDEX TERMS adverse drug reaction autoimmune disease case report clinical trial controlled clinical trial diagnosis drug resistance drug therapy female gene expression gene mutation genetic predisposition germ line headache human infusion peritoneum cancer phase 1 clinical trial phase 2 clinical trial side effect therapy effect toxicity treatment response tumor volume x-ray computed tomography CAS REGISTRY NUMBERS platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616885467 DOI 10.1016/j.ygyno.2017.03.234 FULL TEXT LINK http://dx.doi.org/10.1016/j.ygyno.2017.03.234 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 55 TITLE Novel combination immunotherapy with MUC1 vaccination and immune checkpoint blockade in ovarian cancer AUTHOR NAMES Grabosch S. Zeng F. Ma T. Zhang L. Guido E. Tseng G. Edwards R.P. Vlad A. Brozick J. AUTHOR ADDRESSES (Grabosch S.; Edwards R.P.) Magee-Womens Hospital of UPMC, Pittsburgh, United States. (Zeng F.; Zhang L.; Guido E.; Vlad A.; Brozick J.) Magee-Womens Research Institute, Pittsburgh, United States. (Ma T.; Tseng G.) University of Pittsburgh, Pittsburgh, United States. CORRESPONDENCE ADDRESS S. Grabosch, Magee-Womens Hospital of UPMC, Pittsburgh, United States. SOURCE Gynecologic Oncology (2017) 145 Supplement 1 (86). Date of Publication: 1 Jun 2017 CONFERENCE NAME 48th Annual Meeting on Women's Cancer of the Society of Gynecologic Oncology, SGO 2017 CONFERENCE LOCATION National Harbor, MD, United States CONFERENCE DATE 2017-03-12 to 2017-03-15 ISSN 1095-6859 BOOK PUBLISHER Academic Press Inc. ABSTRACT Objective: Studies from our group and others have demonstrated a role for immune checkpoint blockade in ovarian cancer (OVCA); however, the response was not fully protective. MUC1 is tumorassociated antigen overexpressed in 80% of epithelial OVCA. MUC1 vaccines have been widely tested and show a very good safety profile. We postulate that a novel combined immune modulation with PD-L1 immune checkpoint blockade and MUC1 vaccination will have a synergistic effect and enhanced antitumor activity. Method: MUC1 transgenic mice were challenged intraperitoneally with 800,000 MUC1-expressing, syngeneic 2F8 ovarian tumor cells. Mice were treated with either MUC1 peptide with Ampligen, anti-PDL1 antibody, both drugs (M/P), or PBS/rat IgG as control every 2 weeks for 3 treatments and sacrificed 3 days after last treatment. Splenocytes were analyzed by flow cytometry for CD8 degranulation in response to MUC1 peptide and fluctuations in other immune markers. Nanostring analysis of splenocytes and tumors for 770 immune genes associated with cancer identified differentially expressed (DE) genes in response to treatment. Immunhistochemistry was performed on tumor sections to assess immune infiltration. Results: Combination M/P (but not single agent) treatment resulted in significant survival over control treated mice (P=0.0246). Nanostring analysis identified 66 DE genes consistent with cytotoxic activity in splenocytes from M/P mice versus control including CD8, CD3, and granzyme. Between tumors and splenocytes from M/P mice, 137 DE genes identified tight clustering. Exposure to MUC1 peptide resulted in higher median expression of CD107a in the M/P group consistent with degranulation and greater expression of IFN-g. Tumors from M/P mice had lower regulatory T cell infiltration and a more favorable CD8 to FOXP3 ratio. Conclusion: A 2-pronged immunotherapy treatment using the novel combination of MUC1 vaccination and anti-PD-L1 immune checkpoint blockade improves survival and induces an antitumor cytotoxic immune gene signature. The DE genes between the tumor-infiltrating immune cells and splenocytes further support the need to study the local tumor microenvironment with biomarker analysis. These immunotherapies are being actively explored in clinical trials individually, and our study represents high translational potential for a combination clinical trial. EMTREE DRUG INDEX TERMS antibody biological marker CD3 antigen CD8 antigen endogenous compound gamma interferon granzyme immunoglobulin G lysosome associated membrane protein 1 peptide programmed death 1 ligand 1 rintatolimod transcription factor FOXP3 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female immunotherapy ovary cancer vaccination EMTREE MEDICAL INDEX TERMS animal cell animal experiment animal model antineoplastic activity cancer epidemiology cell infiltration controlled study cytotoxicity degranulation drug combination exposure flow cytometry gene expression genetic marker genetic predisposition immunocompetent cell immunomodulation mouse nonhuman regulatory T lymphocyte spleen cell transgenic mouse tumor microenvironment CAS REGISTRY NUMBERS gamma interferon (82115-62-6) immunoglobulin G (97794-27-9) rintatolimod (38640-92-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616885308 DOI 10.1016/j.ygyno.2017.03.202 FULL TEXT LINK http://dx.doi.org/10.1016/j.ygyno.2017.03.202 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 56 TITLE Pembrolizumab induced auto-immune diabetes and hepatitis AUTHOR NAMES Reslan Z. Paull D. AUTHOR ADDRESSES (Reslan Z.; Paull D.) Royal North Shore Hospital, St Leonards, Australia. CORRESPONDENCE ADDRESS Z. Reslan, Royal North Shore Hospital, St Leonards, Australia. SOURCE Journal of Oncology Pharmacy Practice (2017) 23 Supplement 1 (11). Date of Publication: 1 Jun 2017 CONFERENCE NAME 16th Symposium of the International Society of Oncology Pharmacy Practitioners CONFERENCE LOCATION Budapest, Hungary CONFERENCE DATE 2017-04-26 to 2017-04-29 ISSN 1477-092X BOOK PUBLISHER SAGE Publications Ltd ABSTRACT Objective/purpose: Immunotherapy for metastatic melanoma has improved response rates and progression- free survival significantly compared to traditional chemotherapy. However, they come with unique side effects. Unlike traditional chemotherapy, immunotherapy including pembrolizumab (a Programed Death-1 [PD-1] Inhibitor) cause autoimmune side effects. The most common side effects include: colitis, thyroiditis and hepatitis. There are emerging reports of unique auto-immune side effects as these agents are being more widely used for more cancers. Study design/methods: To report a case of pembrolizumab- induced auto-immune diabetes and hepatitis, in a patient with metastatic melanoma. Results/key findings: Clinical details: A 79-year-old Caucasian male admitted for deranged liver function tests and high blood sugar levels. History of metastatic melanoma (diagnosed 2014, recurrence in 2016, with spinal metastases), macular degeneration and hypertension. Has had five cycles of pembrolizumab. Outcomes: Patient was treated with a weaning dose of prednisolone (starting with 100 mg daily) for hepatitis and was started on a long-acting (basal) and short-acting (bolus) insulin combination to control blood sugar levels and prevent ketoacidosis. Conclusion/recommendations: New emerging immunotherapy treatments are changing the outcomes of patients with metastatic melanoma; however, they have a different side effect profile to traditional chemotherapy agents. Health care professionals and patients should monitor for signs and symptoms of auto-immune side effects including hepatitis, thyroiditis, colitis and hypophysitis. Pharmacists are in an ideal position to monitor for signs and symptoms of immune-related toxicities and should use their expertise to improve patient care and educate other health care professionals. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS insulin prednisolone EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) diabetes mellitus hepatitis A EMTREE MEDICAL INDEX TERMS adverse drug reaction aged case report Caucasian chemotherapy colitis diagnosis disease duration drug therapy glucose blood level human hypertension hypophysitis immunotherapy ketoacidosis liver function test macular degeneration male metastatic melanoma patient care pharmacist prevention relapse side effect spinal cord metastasis study design symptom thyroiditis toxicity weaning CAS REGISTRY NUMBERS insulin (9004-10-8) pembrolizumab (1374853-91-4) prednisolone (50-24-8) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616624284 DOI 10.1177/1078155217691227 FULL TEXT LINK http://dx.doi.org/10.1177/1078155217691227 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 57 TITLE AntiPD1 antibody pembrolizumab treatment of metastatic thymic cancer as antigenic trigger for myasthenia gravis AUTHOR NAMES Baten A. Yusuf N. Tornatore C. AUTHOR ADDRESSES (Baten A.) Neurology, MedStar Georgetown University Hospital, Washington, United States. (Yusuf N.; Tornatore C.) MedStarGeorgetown University Hospital, Washington, United States. CORRESPONDENCE ADDRESS A. Baten, Neurology, MedStar Georgetown University Hospital, Washington, United States. SOURCE Neurology (2017) 88:16 Supplement 1. Date of Publication: 1 Apr 2017 CONFERENCE NAME 69th American Academy of Neurology Annual Meeting, AAN 2017 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2017-04-22 to 2017-04-28 ISSN 1526-632X BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Objective: To report on the acute onset of myasthenic syndrome in a patient during treatment with programmed death1 (PD1) inhibitor monoclonal antibody pembrolizumab for the treatment of stage IV thymic cancer. Background: Anti-PD1 drugs have demonstrated clinical success in the treatment of melanoma and now of other cancers as well. Pembrolizumab, the monoclonal antibody prescribed in the patient discussed, was approved by the FDA in September 2014 for use in metastatic melanoma. As these medications become more commonly prescribed, we learn that the disruption of the immune checkpoint molecules can result in imbalances in immunologic tolerance which may clinically manifest as autoimmune side effects. In essence, these medications ramp up the immune system and thus have been found to cause immunerelated adverse events (irAE's). Design/Methods: Case report of a patient treated with Pembrolizumab for Stage IV thymic cancer. Results: A 36year old Caucasian male with a history of inoperable thymic cancer with local invasion and lung metastasis presented with shortness of breath and vertical diplopia which had progressively worsened over a week. He demonstrated bulbar and skeletal neuromuscular weakness characterized by a nasal quality to his voice, facial diplegia, vertical diplopia and limb weakness which was more profound in proximal muscle groups and in upper extremities. Acetylcholine receptor antibody was positive (0.45 nmol/L, nl <0.02nmol/L). EMG/NCS showed a marked increase in spontaneous activity from all muscles tested including the face. Recruitment patterns and motor unit morphology were normal except for early recruitment for level of effort from hand. Treatment with oral steroids led to prompt resolution of symptoms. Conclusions: We report the first case of a patient with thymic cancer who developed a clinical syndrome consistent with myasthenia gravis following treatment with a PD1 antagonist. We hypothesize that antigens on the thymic cancer were the Pembrolizumabinduced trigger for the development of myasthenia gravis. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) cholinergic receptor antibody pembrolizumab EMTREE DRUG INDEX TERMS endogenous compound programmed death 1 receptor steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) myasthenia gravis thymus cancer EMTREE MEDICAL INDEX TERMS adult adverse drug reaction case report Caucasian diplopia drug therapy dyspnea facial nerve paralysis human immune system immunological tolerance limb weakness lung metastasis male metastatic melanoma morphology neurophysiological recruitment side effect symptom upper limb voice CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616550400 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 58 TITLE Time course observation of thyroid-associated autoantibody and hormone and profiles in patients receiving nivolumab for metastatic melanoma AUTHOR NAMES Sato Y. Hayakawa J. Ohyama M. AUTHOR ADDRESSES (Sato Y.; Hayakawa J.; Ohyama M.) Department of Dermatology, Kyorin University School of Medicine, Shinkawa, Mitaka-shi, Tokyo, Japan. CORRESPONDENCE ADDRESS Y. Sato, Department of Dermatology, Kyorin University School of Medicine, Shinkawa, Mitaka-shi, Tokyo, Japan. SOURCE Australasian Journal of Dermatology (2016) 57 Supplement 2 (38). Date of Publication: 1 Nov 2016 CONFERENCE NAME Asia-Pacific Combined Dermatology Research Conference 2016 CONFERENCE LOCATION Noosa, QLD, Australia CONFERENCE DATE 2016-08-25 to 2016-08-28 ISSN 1440-0960 BOOK PUBLISHER Blackwell Publishing ABSTRACT Nivolumab, an anti-programmed death-1 specific monoclonal antibody, exhibits antitumor effect by enhancing host immunoreactivity against tumors and has been known to induce autoimmune adverse events including thyroid dysfunction. To better characterize sequential changes in thyroid-associated hormone and autoantibody profiles, we conducted time course analysis in 4 cases of metastatic melanoma patients treated with nivolumab. One out of 4 cases had serological evidence of positive antithyroglobulins (anti-Tg) and antithyroid peroxidase antibodies (anti-TPO) with normal free T3, free T4 and thyroid-stimulating hormone levels prior to nivolumab exposure. Intriguingly, increase in anti-Tg and-TPO antibody levels accompanied by rise in free T3 and T4 was detected in all cases 3-7 weeks after the first nivolumab administration. Importantly, some linearity between pretreatment anti-Tg and-TPO levels and the extent of posttreatment thyroid dysfunction was detected. Of note, the case with the highest initial antibody levels demonstrated remarkably elevated anti-Tg and-TPO antibody levels within 3 weeks and developed Hashimotos disease with eyelid edema and severe general fatigue 10 weeks after the treatment. In other three cases without clinical signs of hypothyroidism, the rapidity and the peak of anti-thyroid autoantibody production, which remained within normal limits, correlated with pretreatment autoantibody levels. Further accumulation of the cases is necessary however, these findings suggested that thyroid autoantibody levels before the initiation of nivolumab treatment might predict a potential risk for developing thyroid dysfunction represented by painless thyroiditis syndrome and Hashimotos disease. Thus, the evaluation prior to nivolumab administration would enable better management of thyroid-related adverse events. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) hormone nivolumab thyroglobulin antibody EMTREE DRUG INDEX TERMS antithyroid agent endogenous compound peroxidase thyroid antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female male metastatic melanoma EMTREE MEDICAL INDEX TERMS adverse drug reaction case report clinical trial drug therapy exposure eyelid edema fatigue free liothyronine index free thyroxine index gene expression Hashimoto disease human hypothyroidism side effect syndrome CAS REGISTRY NUMBERS nivolumab (946414-94-4) peroxidase (9003-99-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616392739 DOI 10.1111/ajd.12584 FULL TEXT LINK http://dx.doi.org/10.1111/ajd.12584 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 59 TITLE Endocrinological side-effects of nivolumab in advanced non-small cell lung cancer AUTHOR NAMES Rossi G. Albertelli M. Nazzari E. Rijavec E. Genova C. Barletta G. Biello F. Maggiori C. Tagliamento M. Dal Bello M.G. Ferone D. Grossi F. AUTHOR ADDRESSES (Rossi G.; Rijavec E.; Genova C.; Barletta G.; Biello F.; Maggiori C.; Tagliamento M.; Dal Bello M.G.; Grossi F.) Lung Cancer Unit, IRCCS AOU San Martino - IST, Genova, Italy. (Albertelli M.; Nazzari E.; Ferone D.) Department of Internal Medicine, RCCS AOU San Martino - IST, University of Genova, Genova, Italy. CORRESPONDENCE ADDRESS G. Rossi, Lung Cancer Unit, IRCCS AOU San Martino - IST, Genova, Italy. SOURCE European Journal of Clinical Investigation (2017) 47 Supplement 1 (161-162). Date of Publication: 1 May 2017 CONFERENCE NAME 51st Annual Scientific Meeting of the European Society for Clinical Investigation CONFERENCE LOCATION Genoa, Italy CONFERENCE DATE 2017-05-17 to 2017-05-19 ISSN 1365-2362 BOOK PUBLISHER Blackwell Publishing Ltd ABSTRACT Background: Immune check-point inhibitors (ICPIs) are considered well-tolerated drugs. Previous experiences with ipilimumab in advanced melanoma have shown possible endocrine toxicities, while less data have been collected about nivolumab. ICPIs act by blocking inhibitory signaling and, therefore, enhancing T-cell activity against tumor cells. This mechanism might result in impaired self-tolerance with subsequent development of immune-related adverse events (irAEs), with particular regard to endocrine toxicities. Methods: From May 2015 to April 2016, 74 patients with advanced pretreated NSCLC (52 Male, 22 Female, mean age: 64 years) received at least one dose of nivolumab. Blood samples were collected at baseline and at each cycle in order to dose TSH, ACTH, cortisol, Prolactin [PRL], testosterone and autoantibodies (ATG, ATPO and anti-TSH). Thyroid morphology was evaluated by ultrasonography at baseline, eventually repeated if TSH anomaly was observed. Results: Thyroid function was assessed in all 74 patients. During treatment, 4 patients developed transient thyrotoxicosis evolving to hypothyroidism in 75% of cases. All patients with transient thyrotoxicosis had increased thyroid autoantibodies; 8 patients developed hypothyroidism, with negative thyroid autoimmunity. Adrenocortical axis was evaluable in 55 patients, of which 14 receiving corticosteroids (equivalent of 10 mg/day of prednisone). Among the remaining 31 patients, 7 showed significant cortisol alterations (2 elevated, 5 reduced). Gonadal axis was evaluated in 38 male patients, and no significant change was observed. PRL was assessed in 56 patients; among these, 10 were treated with drugs known to increase PRL levels. 20 patients had at least one elevated PRL value, only 8 showed significantly increased values (3 occurred during therapy). Conclusion: Thyroid function abnormalities seem the major endocrine adverse event related to nivolumab. With respect to other hormonal axes, further conclusions might be drawn after a longer follow-up, due to the heterogeneity of available results and the presence of interfering factors. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS corticotropin endogenous compound hydrocortisone prednisone prolactin testosterone thyroid antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) non small cell lung cancer EMTREE MEDICAL INDEX TERMS adult adverse drug reaction autoimmunity blood clinical trial congenital malformation drug therapy echography female follow up gonad human hypothyroidism immunological tolerance major clinical study male middle aged morphology participant observation side effect thyroid function thyrotoxicosis toxicity CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) nivolumab (946414-94-4) prednisone (53-03-2) prolactin (12585-34-1, 50647-00-2, 9002-62-4) testosterone (58-22-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616278078 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 60 TITLE Incidence of thyroid immune-related adverse events in melanoma patients treated with pembrolizumab in an expanded access program AUTHOR NAMES De Filette J. Yanina J. Max S. Hendrik E. Brigitte V. Bart N. Bert B. AUTHOR ADDRESSES (De Filette J.; Brigitte V.; Bert B.) Department of Endocrinology, Brussels, Belgium. (Yanina J.; Max S.; Bart N.) Medical Oncology and 3Nuclear Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, Brussels, Belgium. (Hendrik E.) CORRESPONDENCE ADDRESS J. De Filette, Department of Endocrinology, Brussels, Belgium. SOURCE Acta Clinica Belgica: International Journal of Clinical and Laboratory Medicine (2016) 71 Supplement 3 (19). Date of Publication: 2016 CONFERENCE NAME 26th Meeting of the Belgian Endocrine Society CONFERENCE LOCATION Brussels, Belgium CONFERENCE DATE 2016-10-14 to 2016-10-15 ISSN 2295-3337 BOOK PUBLISHER Taylor and Francis Ltd. ABSTRACT Context: Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 receptor (PD-1) monoclonal antibody (mAb), remains to be fully characterized. Objective: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction. Design and setting: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access programme at a referral oncology centre. 18Fluorodeoxyglucose uptake on positron emission tomography/computed tomography ((18)FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis. Patients: 99 patients with advanced melanoma (aged 26.3-93.6 years; 63.6% females) who received at least 1 administration of pembrolizumab. Main Outcome Measures: Patient characteristics, thyroid function (TSH, fT4), thyroid autoantibodies and (18)FDG-PET/CT. Results: 18 adverse events of thyroid dysfunction were observed in 17 patients. Hyperthyroidism occurred in 12 patients of which 9 evolved to hypothyroidism. Isolated hypothyroidism was present in six patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in 4 of 10 cases. Diffuse increased (18)FDG uptake by the thyroid gland was observed in all 7 evaluable hyperthyroid patients who progressed to hypothyroidism. Conclusions: Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and hyperthyroidism related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 mAb therapy. Hyperthyroidism compatible with inflammatory thyroiditis was associated with diffuse increased (18)FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated together with histopathological correlates. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS endogenous compound levothyroxine programmed death 1 receptor thyroid antibody thyrotropin unclassified drug EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) compassionate use melanoma side effect EMTREE MEDICAL INDEX TERMS adult adverse drug reaction clinical trial drug therapy female human hyperthyroidism hypothyroidism major clinical study male oncology patient referral positron emission tomography-computed tomography thyroid function test thyroiditis CAS REGISTRY NUMBERS levothyroxine (51-48-9) pembrolizumab (1374853-91-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616191792 DOI 10.1080/17843286.2016.1267486 FULL TEXT LINK http://dx.doi.org/10.1080/17843286.2016.1267486 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 61 TITLE Management of endocrinopathies associated with nivolumab and ipilimumab combination therapy in solid tumors AUTHOR NAMES Wood L. Davies M. Rubin K. Madden K. Brennan L. Dahl N. Walker D. Gagnier P. Li X. Kottschade L. AUTHOR ADDRESSES (Wood L.) Cleveland Clinic Cancer Center, Cleveland, United States. (Davies M.) Yale University, School of Medicine, New Haven, United States. (Rubin K.) Massachusetts General Hospital, Boston, United States. (Madden K.) New York University Medical Oncology, New York, United States. (Brennan L.) UC Davis Comprehensive Cancer Center, Sacramento, United States. (Dahl N.; Kottschade L.) Mayo Clinic, Rochester, United States. (Walker D.; Li X.) Bristol-Myers Squibb, New York, United States. (Gagnier P.) Bristol-Myers Squibb, Wallingford, United States. CORRESPONDENCE ADDRESS L. Wood, Cleveland Clinic Cancer Center, Cleveland, United States. SOURCE BJU International (2016) 118 Supplement 5 (29). Date of Publication: 1 Dec 2016 CONFERENCE NAME 15th International Kidney Cancer Symposium CONFERENCE LOCATION Miami, FL, United States CONFERENCE DATE 2016-11-04 to 2016-11-05 ISSN 1464-410X BOOK PUBLISHER Blackwell Publishing Ltd ABSTRACT Background: Combination therapy with nivolumab and ipilimumab (N + I) is approved for first- line treatment of advanced melanoma (MEL). Recent phase I studies have shown promising efficacy with N + I in patients with non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (RCC). With N + I, select adverse events (ie, immune-related AEs) most commonly affect the skin, gastrointestinal tract, endocrine organs, and liver. Unlike other immune-related AEs, endocrinopathies can persist despite discontinuation or completion of therapy. Here, we review endocrine select AEs associated with N + I in solid tumors and provide practical guidance regarding their management. Methods: Safety data were included from phase II (CheckMate 069) and phase III (CheckMate 067) studies for MEL, and phase I studies for NSCLC (CheckMate 012) and RCC (CheckMate 016). Data are reported for nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W × 4 (N1I3) for MEL, nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W (N3I1) for NSCLC, and N3I1 or N1I3 for RCC, followed by nivolumab Q2W. Patients were treated until disease progression, unacceptable toxicity, or withdrawal of consent. Results: In patients with MEL who received N + I combination therapy, ∼32% experienced any treatment-related endocrine select AEs, of which 5-6% were grade 3-4 (Table). Endocrine select AEs of any grade occurred in 21% of patients with NSCLC, 28% of patients with RCC who received N3I1, and 43% of patients with RCC who received N1I3. The most common treatment-related endocrine select AEs across tumor types were hypothyroidism, hyperthyroidism, and adrenal insufficiency. No treatment-related grade 5 endocrinopathies were observed with N + I in any study. Median time to onset for endocrine select AEs was 6 weeks in MEL. Only 2-3% of patients discontinued due to treatment-related endocrine select AEs. Some patients (typically those with lower grade AEs) can continue nivolumab if the AEs are related to ipilimumab. Persistent or worsening fatigue, headaches, and nausea are common symptoms, and may be associated with hypophysitis. Baseline labs (including thyroid- stimulating hormone) should be performed. MRI with pituitary cut can be used to evaluate potential immunemediated hypophysitis. Patients with thyroid dysfunction need symptomatic management and thyroid hormone replacement, and those with adrenal insufficiency may require long-term glucocorticoid replacement. Conclusions: Endocrine select AEs are manageable with established treatment algorithms. Given the unique nature of endocrine AEs, early identification is critical and a multidisciplinary team approach is required to effectively manage these patients. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab nivolumab EMTREE DRUG INDEX TERMS endogenous compound glucocorticoid thyroid hormone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency non small cell lung cancer EMTREE MEDICAL INDEX TERMS adverse drug reaction clinical article clinical trial controlled clinical trial controlled study disease course drug combination drug therapy drug withdrawal fatigue female headache human hyperthyroidism hypophysitis hypothyroidism kidney metastasis male melanoma nausea nuclear magnetic resonance imaging phase 1 clinical trial phase 2 clinical trial safety side effect symptom toxicity CAS REGISTRY NUMBERS ipilimumab (477202-00-9) nivolumab (946414-94-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L616030205 DOI 10.1111/bju.13694 FULL TEXT LINK http://dx.doi.org/10.1111/bju.13694 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 62 TITLE Update: Autoimmune side effects of ipiliumumab and pembrolizumab in metastatic melanoma. Case study of patient with hypophysitis, pneumonitis, colitis, vitiligo AUTHOR NAMES Harris V. Guminski A. Smith S.D. AUTHOR ADDRESSES (Harris V.; Smith S.D.) Royal North Shore Hospital, St Leonards, Australia. (Harris V.; Smith S.D.) Northern Clinical School, University of Sydney, St Leonards, Australia. (Guminski A.) Oncology, Melanoma Institute of Australia, Wollstonecraft, Australia. (Smith S.D.) Gosford Skin and Cancer Centre, Gosford, Australia. CORRESPONDENCE ADDRESS V. Harris, Royal North Shore Hospital, St Leonards, Australia. SOURCE Australasian Journal of Dermatology (2017) 58 Supplement 1 (60). Date of Publication: 1 May 2017 CONFERENCE NAME 50th Annual Scientific Meeting of the Australasian College of Dermatologists CONFERENCE LOCATION Sydney, NSW, Australia CONFERENCE DATE 2017-05-06 to 2017-05-09 ISSN 1440-0960 BOOK PUBLISHER Blackwell Publishing ABSTRACT Advances in immunotherapy and molecular targeted therapy have dramatically altered prognosis for patients with advanced melanoma. This case report describes sequela of autoimmune side effects experienced by a patient following Ipilimumab and Pemprobolizumab. Ipilimumab is monoclonal antibody that works to activate the immune system by targeting Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a protein receptor that down regulates the immune system. Pembrolizumab is a humanised IgG4 monoclonal antibody directed against the programmed death cell receptor 1 (PD1), an inhibitory receptor expressed by T cells. Both agents have been used in patients with metastatic melanoma with recent promising results. This is a case report of a patient treated with both agents for metastatic melanoma BRAF wild type with NRAS Q61R mutation and multiple metastases at baseline; right upper lobe, paratracheal node and liver. He had background of hypercholesterolemia, bilateral deafness secondary to viral infection, mild Chronic Obstructive Pulmonary Disease and was a previous smoker. Patient had combined Pembrolizumab/Ipilimumab therapy for 8 months with only Ipilimubab for final 2 months. Therapy was ceased due to severe side effects; hypophysitis (inflammation of pituitary gland) and pneumonitis. Other side effects included colitis and vitiligo. A recent study showed 25% of cohort treated with Pembrolizumab developed vitiligo and raised the possibility of an association with clinical benefit.(1) There are numerous immune related side effects such as vitiligo that create a new set of challenges for dermatologists, who must develop a working knowledge of these agents, in order to best manage patients in a multidisciplinary setting. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS B Raf kinase cell receptor endogenous compound immunoglobulin G4 ipilimumab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) colitis hypophysitis metastatic melanoma pneumonia vitiligo EMTREE MEDICAL INDEX TERMS case report cell death chronic obstructive lung disease clinical trial controlled study dermatologist drug combination drug therapy gene mutation hearing impairment human hypercholesterolemia liver male metastasis oncogene N ras side effect smoking T lymphocyte virus infection wild type CAS REGISTRY NUMBERS ipilimumab (477202-00-9) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L615731997 DOI 10.1111/ajd.12652 FULL TEXT LINK http://dx.doi.org/10.1111/ajd.12652 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 63 TITLE Hypophysitis and adrenal insufficiency secondary to ipilimumab and nivolumab: A nearly life threatening side effect of novel immunotherapy agents AUTHOR NAMES Bhalla S. Hauck K. AUTHOR ADDRESSES (Hauck K.) NYU Langone Medical Center, Brooklyn, United States. (Bhalla S.) NYU School of Medicine, New York, United States. CORRESPONDENCE ADDRESS S. Bhalla, NYU School of Medicine, New York, United States. SOURCE Journal of General Internal Medicine (2017) 32:2 Supplement 1 (S514). Date of Publication: 1 Apr 2017 CONFERENCE NAME 40th Annual Meeting of the Society of General Internal Medicine, SGIM 2017 CONFERENCE LOCATION Washington, DC, United States CONFERENCE DATE 2017-04-19 to 2017-04-22 ISSN 0884-8734 BOOK PUBLISHER Springer New York LLC ABSTRACT LEARNING OBJECTIVE #1: Discuss the clinical utility and mechanism of action of a widely used novel immunotherapeutic agents. LEARNING OBJECTIVE #2: Highlight the incidence of endocrinopathies associated with Ipilimumab and Nivolumab. CASE: A 70 year old female with metastatic melanoma presented to the emergency department with fatigue and lethargy for one month. She had recently completed 6 cycles of Nivolumab and Ipilimumab and was currently receiving Nivolumab monotherapy. Over the past month she had worsening fatigue associated with nausea and decreased appetite. Lab work one week prior to admission was significant for newly elevated TSH and low T4, and thyroid replacement therapy was initiated. On the day of admission, she had a syncopal episode at home prompting presentation. On arrival, she was hypotensive to 89/57. Lab work was significant for hyponatremia, hypokalemia, and hypochloremia. Due to concern for adrenal insufficiency, she was started on stress dose hydrocortisone. An AM serum cortisol was 1.5 and ACTH level was undetectable. FSH and LH levels were also low. An MRI of the brain was notable for enhancement of the pituitary gland suggestive of hypophysitis, which was likely a side effect of her immunotherapy. IMPACT: Ipilimumab and Nivolumab are novel immunotherapeutic agents used in the treatment of melanoma, with research investigating their use into other malignancies as well. Endocrinopathies are relatively common side effects of these agents, especially when given as combination therapy. Nonspecific complaints, such as fatigue and nausea in our patient, should warrant a thorough investigation for endocrinopathies in patients with treatment exposure to ipilimumab and/or nivolumab. DISCUSSION: Nivolumab and Ipilimumab are novel immunotherapeutic agents that are currently used for metastatic melanoma and squamous lung carcinoma. Nivolumab antagonizes the binding of Programmed Cell Death Ligand 1 to the programmed cell death 1 receptor (PD-1), activation of which would normally promote T-cell apoptosis. Ipilimumab antagonizes the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), preventing down regulation cytotoxic T lymphocytes. Endocrinopathies are relatively common side effects of checkpoint inhibitors and are thought to be result of auto-immune inflammation. They can manifest as primary hyper/hypothyroidism, primary adrenal insufficiency and/or hypophysitis thereby affecting the multiple hormonal systems. A retrospective review from Memorial Sloan Kettering showed an incidence of hypophysitis of 8 and thyroiditis of 6% following treatment with ipilimumab. The incidence of hypophysitis and thyroiditis increased to 9 and 22% respectively in patients who received combination therapy with ipilimumab and nivolumab. Our patient seemingly developed primary hypothyroidism and hypophysitis causing a secondary adrenal insufficiency secondary to her combination therapy. The initiation of levothyroxine therapy likely precipitated her adrenal insufficiency leading to her syncopal event. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab nivolumab EMTREE DRUG INDEX TERMS antihypertensive agent corticotropin cytotoxic T lymphocyte antigen 4 endogenous compound hydrocortisone levothyroxine ligand programmed death 1 receptor thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency hypophysitis immunotherapy EMTREE MEDICAL INDEX TERMS Addison disease adverse drug reaction aged apoptosis brain case report chemical binding chemical stress clinical trial cytotoxic T lymphocyte decreased appetite down regulation drug combination drug therapy emergency ward exposure fatigue female gene inactivation human human tissue hydrocortisone blood level hypochloremia hypokalemia hyponatremia hypothyroidism lethargy lung carcinoma metastatic melanoma monotherapy nausea nuclear magnetic resonance imaging retrospective study side effect squamous cell carcinoma substitution therapy thinking thyroiditis CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) levothyroxine (51-48-9) nivolumab (946414-94-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L615581292 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 64 TITLE Safety and clinical activity of avelumab (MSB0010718C; anti-PD-l1) in patients with advanced thymic epithelial tumors (TETs) AUTHOR NAMES Rajan A. Heery C. Mammen A. Pittaluga S. Lepone L. Donahue R. Grenga I. Schlom J. Gulley J. Hassan R. AUTHOR ADDRESSES (Rajan A.; Hassan R.) Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, United States. (Heery C.; Lepone L.; Donahue R.; Grenga I.; Schlom J.; Gulley J.) Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, United States. (Mammen A.) National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States. (Pittaluga S.) Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, United States. CORRESPONDENCE ADDRESS A. Rajan, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, United States. SOURCE Journal of Thoracic Oncology (2017) 12:1 Supplement 1 (S314-S315). Date of Publication: 1 Jan 2017 CONFERENCE NAME 17th World Conference of the International Association for the Study of Lung Cancer, IASLC 2016 CONFERENCE LOCATION Vienna, Austria CONFERENCE DATE 2016-12-04 to 2016-12-07 ISSN 1556-1380 BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Background: Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 antibody under clinical development. We report safety and clinical activity in patients with relapsed TETs enrolled in a phase I trial (NCT01772004). Methods: Patients previously treated with one or more standard therapies, no prior immune checkpoint inhibitors, and with no history of autoimmune disease were eligible. Treatment consisted of avelumab at doses of 10-20 mg/kg iv q2 weeks until disease progression or toxicity. Responses were assessed q6 weeks by RECIST 1.1. Correlative studies included evaluation of tumor cell PD-L1 expression and peripheral blood immune subset analysis. Results: 7 patients with thymoma and 1 with thymic carcinoma (TC) were treated with avelumab; 3 patients with thymoma (2 B3, 1 B2/B3) received avelumab 20 mg/kg; 4 patients with thymoma (1 B1, 3 B2) and 1 TC received 10 mg/kg. Two (29%) patients with thymoma had a confirmed partial response (PR;1 at 20 mg/kg, and 1 at 10 mg/kg), 2 (29%) had unconfirmed PRs, 2 (29%) stable disease (SD) and 1 (14%) progressive disease; the TC patient had SD. Most adverse events (AEs) were mild (grade 1 or 2). Grade 3 and 4 AEs were observed in 3 (38%) patients each, and included potential immunerelated AEs (irAEs) in 5 cases. irAEs resolved completely with oral steroids in 3 patients, and incompletely in 1 patient. One patient required cyclosporine A for treatment of irAEs. All 4 responders experienced irAEs (myositis in 3 patients, all after 1 dose of avelumab, and enteritis in 1 patient). Pre- and post-treatment tumor biopsies were available for analysis of PD-L1 expression and intratumoral immune infiltrates from three patients treated at 20 mg/kg. In one case the post-treatment biopsy showed necrotic tissue with no viable tumor. In the other two cases diffuse, membranous PD-L1 staining of epithelial cells was seen in both pre- and post-treatment biopsies. The immune infiltrate consisted of immature T cells in pre-treatment tumor samples in both cases. The post-treatment biopsy showed continued presence of immature T cells in one case and a mature CD8+ T cell phenotype in the other case. Decreased CTLA4+ regulatory T cells and decreased ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose. Conclusion: Avelumab is active in patients with recurrent thymoma. Strategies need to be developed to reduce the risk of development of irAEs in response to immune checkpoint inhibitor therapy in patients with thymoma. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS cyclosporine endogenous compound steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) carcinoma safety thymoma EMTREE MEDICAL INDEX TERMS adverse drug reaction autoimmune disease CD8+ T lymphocyte clinical article clinical trial controlled study disease duration drug therapy enteritis epithelium cell gene expression granulocyte human human tissue monocyte myeloid-derived suppressor cell myositis pharmacokinetics phenotype pre T lymphocyte regulatory T lymphocyte response evaluation criteria in solid tumors side effect staining toxicity tumor biopsy tumor cell CAS REGISTRY NUMBERS avelumab (1537032-82-8) cyclosporin A (59865-13-3, 63798-73-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L615338839 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 65 TITLE Efficacy of immune checkpoint inhibitors in large cell neuroendocrine lung cancer: Results from a French retrospective cohort AUTHOR NAMES Giaj Levra M. Mazieres J. Valette C.A. Molinier O. Planchard D. Frappat V. Ferrer L. Toffart A.C. Moro-Sibilot D. AUTHOR ADDRESSES (Giaj Levra M.; Ferrer L.; Toffart A.C.; Moro-Sibilot D.) Michallon Hospital - University Hospital, Grenoble, France. (Mazieres J.) Toulouse University Hospital, Toulouse, France. (Valette C.A.) Centre Hospitalier Sainte Musse, Toulon, France. (Molinier O.) Pneumology, Centre Hospitalier Du Mans, Le Mans, France. (Planchard D.) Medical Oncology, Gustave Roussy, Villejuif, France. (Frappat V.) Pneumology, Centre Hospitalier de Chambery, Chambery, France. CORRESPONDENCE ADDRESS M. Giaj Levra, Michallon Hospital - University Hospital, Grenoble, France. SOURCE Journal of Thoracic Oncology (2017) 12:1 Supplement 1 (S702-S703). Date of Publication: 1 Jan 2017 CONFERENCE NAME 17th World Conference of the International Association for the Study of Lung Cancer, IASLC 2016 CONFERENCE LOCATION Vienna, Austria CONFERENCE DATE 2016-12-04 to 2016-12-07 ISSN 1556-1380 BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Background: Nivolumab and pembrolizumab, two programmed death (PD)-1 immune-checkpointeinhibitor antibodies, demonstrated superiority versus standard chemotherapy in second- third line in both squamous and non-squamous lung cancer. Large cell neuroendocrine lung cancer (LCNEC) is a rare tumour often treated as a small cell lung cancer, but there is not a standard of care after a first line progression. Aim of the study was to assess clinical efficacy of PD-1 inhibitors in these patients. Methods: We retrospectively reviewed all consecutive LCNEC stage IIIB- IV patients treated with nivolumab or pembrolizumab after platinum-based first line therapy between July 2014 and November 2015 in six French centers. Patients were followed until June 2016. The drugs were given in an early access program or a clinical trial. Results: The analysis included 10 patients with advanced stage disease. Eight patients (80%) had a stage IV disease with a median age of 59 [interquartile range (IQR) 55-62] years. The majority were males (n=9; 90%), with good performance status (0-1; 9/90%) and 50% were treated in third line or further. Three patients presented brain metastases. In 5 cases a molecular test was done, finding in one case (20%) a KRAS mutation. Patients received a first line treatment with platinum and etoposide in 8 cases (80%) with a disease control rate of 50%. Nine patients received nivolumab and the PD-L1 status was never performed, while the patient treated with pembrolizumab expressed PD-L1. Patients received a median number of 16 [IQR, 13-18] cycles, 6 showed a partial response (60%), 1 a stable disease (10%). Median PFS was 57 [24-57] weeks. Most of the patients stopped treatment due to disease progression (n=4; 80%), only one for a pulmonary interstitial pneumonia. Conclusion: Our findings suggest that the use of immune- checkpointeinhibitors in LCNEC could be explored in a larger cohort of patients. This treatment could be considered in the scenario of a disease with limited therapeutic strategy. EMTREE DRUG INDEX TERMS endogenous compound etoposide K ras protein nivolumab pembrolizumab platinum programmed death 1 ligand 1 programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) large cell neuroendocrine carcinoma lung cancer EMTREE MEDICAL INDEX TERMS adult brain metastasis cancer staging clinical article clinical trial comparative effectiveness controlled clinical trial controlled study disease control disease course drug therapy gene mutation human interstitial pneumonia male middle aged multicenter study CAS REGISTRY NUMBERS etoposide (33419-42-0) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L615339837 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 66 TITLE Endocrinological side-effects of nivolumab in advanced non-small cell lung cancer AUTHOR NAMES Rossi G. Albertelli M. Nazzari E. Rijavec E. Genova C. Barletta G. Biello F. Maggioni C. Dal Bello M.G. Ferone D. Grossi F. AUTHOR ADDRESSES (Rossi G.; Rijavec E.; Genova C.; Barletta G.; Biello F.; Maggioni C.; Dal Bello M.G.; Ferone D.; Grossi F.) Lung Cancer Unit, San Martino Hospital, National Institute for Cancer Research, Genova, Italy. (Albertelli M.; Nazzari E.) Endocrinology Division, San Martino Hospital, National Institute for Cancer Research, Genova, Italy. CORRESPONDENCE ADDRESS G. Rossi, Lung Cancer Unit, San Martino Hospital, National Institute for Cancer Research, Genova, Italy. SOURCE Journal of Thoracic Oncology (2017) 12:1 Supplement 1 (S1297-S1298). Date of Publication: 1 Jan 2017 CONFERENCE NAME 17th World Conference of the International Association for the Study of Lung Cancer, IASLC 2016 CONFERENCE LOCATION Vienna, Austria CONFERENCE DATE 2016-12-04 to 2016-12-07 ISSN 1556-1380 BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Background: Immune check-point inhibitors (ICPIs) are considered well-tolerated drugs. Previous experience with ipilimumab in advanced melanoma have shown possible endocrine toxicities, while less data have been collected about Nivolumab. ICPIs act by blocking inhibitory signaling and, therefore, enhancing T-cell activity against tumor cells. This mechanism might result in impaired self-tolerance with subsequent development of immune-related adverse events (irAEs), and endocrine toxicities are especially relevant. Methods: From May 2015 to April 2016, 74 patients with advanced pretreated NSCLC (52 Male, 22 Female, mean age: 64 years) received at least one dose of nivolumab (3 mg/Kg every 14 days) within a single-institutional translational research trial. Blood samples were collected at baseline and at each cycle in order to monitor hormone (TSH, ACTH, cortisol, Prolactin[PRL] and testosterone) serum levels and autoantibodies (ATG, ATPO and anti-TSH) formation. Thyroid morphology was evaluated by ultrasonography at baseline, eventually repeated if TSH anomaly was observed. Results: Thyroid function was assessed in all 74 patients. At baseline, 6 patients had impaired thyroid function: 5 with reduced TSH, including two undergone previous thyroidectomy that required reduction in levothyroxine replacement therapy, and 1 with increased TSH. During treatment, 4 patients developed transient thyrotoxicosis evolving to hypothyroidism in 75% of cases. All patients with transient thyrotoxicosis reported increased thyroid autoantibodies; 8 patients developed hypothyroidism, with negative thyroid autoimmunity. Adrenocortical axis was evaluable in 55 subjects, of which 14 under steroid (equivalent of 10 mg of prednisone) therapy (one had partial hypopituitarism). Among the remaining 31 patients, 7 showed significant cortisol alterations (2 elevated, 5 reduced). Gonadal axis was evaluated in 38 male patients; among these, one was taking testosterone replacement therapy for partial hypopituitarism and one was receiving GnRH antagonists. No significant change on gonadal status was observed. PRL was assessed in 56 patients; among these, 10 were treated with drugs known to increase PRL levels; 20 patients had at least one elevated prolactin value, 7 from baseline and 13 developed during treatment. However, only 8 showed significantly increased values (>50 mcg/ L in n=6, developed during therapy in 50% of cases; >100 mcg/L in n=2 from baseline). Conclusion: Thyroid function abnormalities, in particular non-autoimmune hypothyroidism and transient thyrotoxicosis on autoimmune basis, seem the major endocrine adverse event related to nivolumab. With respect to other hormonal axes, further conclusions might be drawn after a longer follow-up, due to the heterogeneity of available results and the presence of interfering factors. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS corticotropin endogenous compound gonadorelin antagonist hormone hydrocortisone levothyroxine prednisone prolactin testosterone thyroid antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) immunotherapy non small cell lung cancer toxicity EMTREE MEDICAL INDEX TERMS adult adverse drug reaction androgen therapy autoimmunity blood clinical trial congenital malformation drug therapy echography female follow up gene expression gene inactivation gonad human human tissue hypopituitarism hypothyroidism immunological tolerance major clinical study male middle aged morphology patient history of thyroidectomy side effect substitution therapy thyroid function thyrotoxicosis translational research CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) levothyroxine (51-48-9) nivolumab (946414-94-4) prednisone (53-03-2) prolactin (12585-34-1, 50647-00-2, 9002-62-4) testosterone (58-22-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L615338159 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 67 TITLE A case with a primary adrenal insufficiency secondary to nivolumab AUTHOR NAMES Coskun N.S.S. Simsir I.Y. Goksel T. AUTHOR ADDRESSES (Coskun N.S.S.; Simsir I.Y.; Goksel T.) CORRESPONDENCE ADDRESS N.S.S. Coskun, SOURCE European Respiratory Journal (2016) 48 Supplement 60. Date of Publication: 1 Sep 2016 CONFERENCE NAME European Respiratory Society Annual Congress 2016 CONFERENCE LOCATION London, United Kingdom CONFERENCE DATE 2016-09-03 to 2016-09-07 ISSN 1399-3003 BOOK PUBLISHER European Respiratory Society ABSTRACT Abstract Immunological therapy in treatment of lung cancer has been introduced effectively. Nivolumab that is anti PD-1 monoclonal antibody has some immunological side effects. 50 years old male was diagnosed stage IV adenocarcinoma with bilaterally adrenal metastasis. The driver mutations (EGFR, ALK, ROS-1) were not detected. He had been treated with 3 lines chemotherapies. He had not responded any chemotherapy. We started nivolumab in the patient. After 10 days from the first therapy, he admitted to Emergency Unit of our hospital with dyspnea, nausea, vomiting, and changes of consciousness. Arterial blood pressure (80/50 mmHg) and randomized blood sugar (60 mg/dl) was low. He had dry mucosa and hyperpigmentation on his skin. We found Urea:93 mg/dl (>50), Creatinin:2.11 mg/dl (>1.5), Sodium:124 mEq/L (<135), Potassium:6.7 mEq/L (>5) in his blood and pH:7.23, pCO2:34.8, HCO3:14.2 (<22) in arterial blood gases. We thought metabolic alkalosis secondary to hyperkalemia and adrenal insufficiency. Adrenocorticothrophic hormone (ACTH) level was 1234 (>50), cortizol level (at 08:00 AM) 0.96 mcg/dl (<10). In Cranial MR, there was no any acute pathology. In abdomen ultrasound, there was no any finding of adrenal bleeding or infection. The diagnosis of primary adrenal insufficiency was thought to be related with immunological side effect of nivolumab. The patient has been treated with intravenous steroid replacement. After the treatment, levels of sodium, potassium, ACTH, blood sugar and blood pressure has been normalized. We have presented a case with primary adrenal insufficiency secondary to nivolumab, as a very rare immunological side effect of this new drug. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS creatinine endogenous compound epidermal growth factor receptor hormone hydrocortisone new drug potassium programmed death 1 receptor reactive oxygen metabolite sodium urea EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) Addison disease EMTREE MEDICAL INDEX TERMS abdomen adenocarcinoma adrenal hemorrhage adrenal insufficiency adrenal metastasis adult adverse drug reaction arterial pressure blood gas carbon dioxide tension case report chemotherapy consciousness controlled clinical trial controlled study diagnosis driver dyspnea emergency ward gene mutation glucose blood level hormone determination human hyperkalemia hyperpigmentation immunotherapy infection lung cancer male metabolic alkalosis middle aged mucosal dryness nausea and vomiting pathology randomized controlled trial side effect thinking ultrasound CAS REGISTRY NUMBERS creatinine (19230-81-0, 60-27-5) epidermal growth factor receptor (79079-06-4) hydrocortisone (50-23-7) nivolumab (946414-94-4) potassium (7440-09-7) sodium (7440-23-5) urea (57-13-6) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L614779908 DOI 10.1183/13993003.congress-2016.PA4853 FULL TEXT LINK http://dx.doi.org/10.1183/13993003.congress-2016.PA4853 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 68 TITLE Acute onset Type 1 diabetes precipitated by Pembrolizumab, an anti-PD-1 monoclonal antibody used as a treatment for melanoma AUTHOR NAMES Farrell C.M. Casasola R. Pearson E.Z. Schofield C. AUTHOR ADDRESSES (Farrell C.M.; Pearson E.Z.; Schofield C.) Diabetes and Endocrinology, Ninewells Hospital, Dundee, United Kingdom. (Casasola R.) Oncology, Ninewells Hospital, Dundee, United Kingdom. CORRESPONDENCE ADDRESS C.M. Farrell, Diabetes and Endocrinology, Ninewells Hospital, Dundee, United Kingdom. SOURCE Diabetic Medicine (2017) 34 Supplement 1 (95). Date of Publication: 1 Mar 2017 CONFERENCE NAME Diabetes UK Professional Conference 2017 CONFERENCE LOCATION Manchester, United Kingdom CONFERENCE DATE 2017-03-08 to 2017-03-10 ISSN 1464-5491 BOOK PUBLISHER Blackwell Publishing Ltd ABSTRACT A 30 year old Caucasian man (DG) with metastatic melanoma was admitted to the oncology unit with 24-hour history of vomiting, polydipsia and polyuria. Biochemistry revealed hyperglycaemia and ketoacidosis (blood glucose 27.5mmol/l, bicarbonate 10mmol/ l ketonuria +++) in a previously normoglycaemic man. Pancreatitis was ruled out. He was treated with fluid and intravenous insulin (85 units/24h) to maintain normoglycaemia. There was no family history of diabetes and he had not received treatment with corticosteroids. CT abdomen and pelvis did not show any pancreatic metastases. DG was receiving palliative immunotherapy with Pembrolizumab; he presented 12 days after the third injection. Pembrolizumab is a monoclonal antibody targeting the co-inhibitory immune checkpoint molecule programmed cell death protein 1(PD-1). PD-1 is a cell surface receptor that is expressed on T cells; it is a key immune regulator which may have a protective role against the development of autoimmune diabetes. PD-1 over expression in mice significantly reduces the incidence of autoimmune diabetes, while inhibition of PD-1 or its ligand rapidly precipitates diabetes in prediabetic mice. DG was commenced on insulin therapy at presentation and continued to require insulin to maintain normoglycaemia. The HbA1c at presentation was 57mmol/mol with undetectable cpeptide. Anti-glutamic acid decarboxylase and islet antigen 2 antibodies were both negative supportive of a non-autoimmune aetiology for the diabetes. There are increasing indications for the use of anti-PD1 immunotherapy in cancer. Physicians and patients should be aware that diabetes may be a rare, but important adverse effect of treatment. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab programmed death 1 receptor EMTREE DRUG INDEX TERMS bicarbonate cell surface receptor corticosteroid endogenous compound glutamate decarboxylase 67 hemoglobin A1c insulin ligand EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) insulin dependent diabetes mellitus metastatic melanoma EMTREE MEDICAL INDEX TERMS abdomen adult animal experiment animal model biochemistry Caucasian drug therapy drug toxicity family study gene inactivation gene overexpression human hyperglycemia immunotherapy impaired glucose tolerance injection insulin treatment ketoacidosis ketonuria liquid male mouse nonhuman oncology pancreas islet pancreas metastasis pancreatitis pelvis physician polydipsia polyuria precipitation T lymphocyte vomiting CAS REGISTRY NUMBERS bicarbonate (144-55-8, 71-52-3) hemoglobin A1c (62572-11-6) insulin (9004-10-8) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L614844944 DOI 10.1111/dme.13302 FULL TEXT LINK http://dx.doi.org/10.1111/dme.13302 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 69 TITLE Fall in TSH by ≥80% is associated with development of ipilimumab-induced hypophysitis AUTHOR NAMES Sheriff N. De Sousa S.M.C. Menzies A.M. Tsang V.H.M. Long G.V. Tonks K.T. AUTHOR ADDRESSES (Sheriff N.; De Sousa S.M.C.) Hormones and Cancer Group, Garvan Institute of Medical Research, Sydney, Australia. (Sheriff N.; Tonks K.T.) St Vincent's Hospital, Darlinghurst, Australia. (De Sousa S.M.C.) Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia. (Menzies A.M.; Long G.V.) Melanoma Institute Australia, Sydney, Australia. (Tsang V.H.M.) Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia. CORRESPONDENCE ADDRESS N. Sheriff, Hormones and Cancer Group, Garvan Institute of Medical Research, Sydney, Australia. SOURCE Clinical Endocrinology (2017) 86 Supplement 1 (36). Date of Publication: 1 Jan 2017 CONFERENCE NAME Endocrine Society of Australia Annual Scientific Meeting 2016 CONFERENCE LOCATION Gold Coast, QLD, Australia CONFERENCE DATE 2016-08-21 to 2016-08-24 ISSN 1365-2265 BOOK PUBLISHER Blackwell Publishing Ltd ABSTRACT Objective: Hypophysitis occurs in up to 25% of patients with melanoma treated with ipilimumab1,2. We aimed to determine if serial routine cortisol measurements could predict hypophysitis. Methods: We performed a retrospective audit of metastatic melanoma patients with pituitary function tests performed during ipilimumab treatment (3 mg/kg IV 3 weekly for 4 doses) at the Melanoma Institute Australia for 16 months to December 2014. Patients were included if they had two or more cortisol measurements prior to sequential doses of ipilimumab. Results: Forty-six of 78 treated patients were included, receiving a total of 163 ipilimumab cycles (median 4 per patient, range 2-4). Nine (20%) developed hypophysitis, a mean of 12.3 ± 1.6 weeks (median 13, range 7.7-18) from the first ipilimumab dose. There was no difference in cortisol levels between those who did and did not develop hypophysitis, after excluding measurements after 11 am, or on glucocorticoid therapy, prior to cycles 1, 2, 3, 4 and after cycle 4 (P = 0.88, 0.98, 0.64, 0.91 and 0.23 respectively). Interestingly, TSH prior to cycle 4 was significantly lower in those who developed hypophysitis (0.31 vs 1.44 mIU/L, P = 0.002), but not cycles 1, 2 and 3 (P = 0.12, 0.88, and 0.11). If TSH fell by ≥80% from baseline at mean 9.1 + /-0.26 weeks from first ipilimumab, prior to cycle 4, odds for developing hypophysitis were 136 (95% CI 6.2-2947, P < 0.0001) compared to TSH fall <80%. The fall in TSH occurred a mean of 3.4 ± 1.4 weeks (range -1.4-9.7) prior to hypophysitis diagnosis. Conclusions: Pre-infusion cortisol levels did not differentiate those at risk of hypophysitis. TSH is less affected by external factors and a ≥ 80% fall in TSH level during ipilimumab therapy is a strong risk factor for concurrent or future development of hypophysitis. Whether TSH levels measured in the weeks between cycles 3 and 4 could predict hypophysitis earlier is unknown. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab thyrotropin EMTREE DRUG INDEX TERMS endogenous compound hydrocortisone EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis EMTREE MEDICAL INDEX TERMS adverse drug reaction Australia cancer epidemiology clinical trial controlled study diagnosis drug therapy gene expression human infusion major clinical study metastatic melanoma pituitary function test risk factor side effect CAS REGISTRY NUMBERS hydrocortisone (50-23-7) ipilimumab (477202-00-9) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L614326797 DOI 10.1111/cen.13259 FULL TEXT LINK http://dx.doi.org/10.1111/cen.13259 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 70 TITLE Pembrolizumab-induced thyroiditis in patients with metastatic melanoma: A novel form of autoimmune thyroid disease AUTHOR NAMES Sweeting A.N. Lomax A. Lim J. Cheng R. McGill N. Lowe P. Shackel N. McNeil C. Chua E. AUTHOR ADDRESSES (Sweeting A.N.; Chua E.) Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia. (Sweeting A.N.; Shackel N.; McNeil C.; Chua E.) Sydney Medical School, University of Sydney, Sydney, Australia. (Sweeting A.N.; Lim J.; Cheng R.; McGill N.; Lowe P.; Shackel N.; McNeil C.; Chua E.) Royal Prince Alfred Hospital, Camperdown, Australia. (Lomax A.; McNeil C.) Chris O'Brien Lifehouse Cancer Centre, Sydney, Australia. CORRESPONDENCE ADDRESS A.N. Sweeting, Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia. SOURCE Clinical Endocrinology (2017) 86 Supplement 1 (34-35). Date of Publication: 1 Jan 2017 CONFERENCE NAME Endocrine Society of Australia Annual Scientific Meeting 2016 CONFERENCE LOCATION Gold Coast, QLD, Australia CONFERENCE DATE 2016-08-21 to 2016-08-24 ISSN 1365-2265 BOOK PUBLISHER Blackwell Publishing Ltd ABSTRACT Introduction: Pembrolizumab is a fully human monoclonal antibody directed against programmed cell death 1, targeting the effector arm of the immune checkpoint pathway1. Pembrolizumab has superseded other immunotherapies as first-line treatment in patients with metastatic melanoma2 however is associated with autoimmune endocrinopathies. The most common of these is thyroid dysfunction, with reported incidence <1-16%3,4, but evidence is limited regarding its presentation and management. Methods: Retrospective review of patients with metastatic melanoma who received pembrolizumab 2 mg/kg intravenously every three weeks through compassionate access, enrolled from November 2013-August 2015. All patients were evaluated at the Chris O'Brien Lifehouse and Department of Endocrinology, Royal Prince Alfred Hospital. Results: Forty-one patients were identified. Median age was 65 (range: 37-90) years and 32 (78%) were male. Median number of pembrolizumab- cycles received was 4 (1-20), with treatment ongoing in 15 patients (37%). Only 15 (37%) of patients were ipilimumab-näve. Immune-related adverse events (irAEs) occurred in 21 (51%) patients: most commonly dermatological (24%) and rheumatological (22%). Hypophysitis was observed in 1 patient but onset correlated with previous ipilimumab. Primary thyroiditis was confirmed in 5 (12%) patients via baseline TFTs and anti-thyroidal antibodies, characterised by asymptomatic hyperthyroidism followed by symptomatic hypothyroidism (figure 1), requiring ongoing thyroxine replacement. Patient characteristics, investigations and treatment are summarised in table 1. Conclusion: Pembrolizumab-induced thyroiditis was characterised by two distinct phases: hyperthyroidism and hypothyroidism by 3 and 9 weeks respectively, post-initiation of pembrolizumab. Considering that the hyperthyroid phase was asymptomatic, and that exposure to radiocontrast, concurrent glucocorticoid therapy for other irAEs or sick euthyroid condition may result in mild biochemical hyperthyroidism, patients should be followed-up closely. Given the persistence and degree of hypothyroidism, patient age and co-morbidities should not preclude initiation of standard (rather than conservative) thyroxine replacement therapy at the onset of biochemical hypothyroidism in these patients, to prevent symptomatic hypothyroidism. (Figure Presented). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS glucocorticoid ipilimumab thyroid antibody thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune thyroiditis metastatic melanoma EMTREE MEDICAL INDEX TERMS adult adverse drug reaction aged clinical article clinical trial comorbidity drug therapy endocrinology exposure female hospital human hyperthyroidism hypophysitis hypothyroidism male prevention retrospective study side effect substitution therapy CAS REGISTRY NUMBERS ipilimumab (477202-00-9) pembrolizumab (1374853-91-4) thyroxine (7488-70-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L614326784 DOI 10.1111/cen.13259 FULL TEXT LINK http://dx.doi.org/10.1111/cen.13259 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 71 TITLE Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC) AUTHOR NAMES Infante J.R. Braiteh F. Emens L.A. Balmanoukian A.S. Oaknin A. Wang Y. Liu B. Molinero L. Fasso M. O'Hear C. Gordon M. AUTHOR ADDRESSES (Infante J.R.) Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, United States. (Braiteh F.) Medicine, Comprehensive Cancer Centers of Nevada, Las Vegas, United States. (Emens L.A.) School of Medicine, Johns Hopkins University, Baltimore, United States. (Balmanoukian A.S.) Medical Oncology, Angeles Clinic, Research Institute, Los Angeles, United States. (Oaknin A.) Vall D'Hebron University Hospital, Institut D'Oncologia, Barcelona, Spain. (Wang Y.; Liu B.) Biostatistics, Genentech, Inc., South San Francisco, United States. (Molinero L.) Oncology Biomarker Department, Genentech, Inc., South San Francisco, United States. (Fasso M.; O'Hear C.) Product Development Oncology, Genentech Inc, South San Francisco, United States. (Gordon M.) Division of Arizona Center for Cancer Care, Pinnacle Oncology Hematology, Scottsdale, United States. CORRESPONDENCE ADDRESS J.R. Infante, Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, United States. SOURCE Annals of Oncology (2016) 27 Supplement 6. Date of Publication: 2016 CONFERENCE NAME 41st European Society for Medical Oncology Congress, ESMO 2016 CONFERENCE LOCATION Copenhagen, Denmark CONFERENCE DATE 2016-10-07 to 2016-10-11 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: OC usually presents at an advanced stage and has high rates of recurrence and mortality. Most pts die of drug-resistant OC within 5 y, highlighting the need for new therapies. As OC with high T cell infiltrates at diagnosis has longer OS, we examined atezolizumab (atezo; anti-PDL1) in pts with recurrent OC. Methods: Pts received atezo IV q3w (0.3-15 mg/kg) in a Ph Ia dose-escalation/ expansion study (NCT01375842) and were treated until loss of clinical benefit. Confirmed ORR and PFS were assessed by RECIST v1.1. PD-L1 status on immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay) and scored as IC0, 1, 2, 3. After dose-escalation, only IC2 or 3 pts were enrolled. Molecular subtyping was performed using nanostring. Results: As of Dec 15, 2015, 12 pts with ECOG PS 0/1 (50%/50%) and median age of 61 y (range 39-72) were evaluable for safety. 11/12 received ≥ 2 lines of therapy. Atezo doses (mg/kg) were: 0.3 (n = 2), 10 (n = 1) and 15 (n = 9). With a median treatment duration of 2.8 mo, 11/12 pts had a treatment-related AE. These were mainly Gr 1-2; fatigue and pain were most common (5 pts each). 2 pts (17%) had a Gr 3 related AE (autoimmune hepatitis; maculopapular rash). There were no Gr 4 or 5 related AEs or AEs leading to withdrawal. Of 9 response-evaluable pts (10-15 mg/kg atezo and ≥ 12 wk followup; 1 pt without RECIST measurable disease at baseline was evaluable for PFS/OS but not response), 2 pts (22%) had a PR. 1 responder had an 8.1 mo DOR and the other remains on study at 16.6+ mo with a 100% reduction in target lesion volume (1 nontarget lesion remained). 5 pts had PD and 2 were nonevaluable. Median PFS was 2.9 mo (95% CI 1.3-5.5). Median OS was 11.3 mo (95% CI 5.5-27.7) and 17.4 mo (95% CI 5.9-27.7) in 9 IC2/3 pts. Of the 10 evaluable for PFS/OS, 1 pt was IC0/1, 9 were IC2/ 3 and all belonged to an RNA-defined immunoreactive subgroup of OC that is associated with T cell activation and high PD-L1 expression. Atezo responders were IC2/3 and had low baseline CA125 levels vs pts who progressed. Conclusions: In this single-agent OC cohort, atezo demonstrated tolerable safety and encouraging clinical activity. Scientifically rational combinations with chemotherapy, targeted therapy or other cancer immunotherapies may augment the clinical benefit of atezo in OC pts. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) atezolizumab EMTREE DRUG INDEX TERMS CA 125 antigen endogenous compound programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female ovary cancer safety EMTREE MEDICAL INDEX TERMS adult aged autoimmune hepatitis cancer immunotherapy cancer size cell infiltration chemotherapy clinical article clinical trial controlled study diagnosis drug therapy drug withdrawal fatigue follow up gene expression gene loss human human tissue immunocompetent cell immunohistochemistry maculopapular rash molecularly targeted therapy pain pharmacokinetics response evaluation criteria in solid tumors T lymphocyte activation treatment duration CAS REGISTRY NUMBERS atezolizumab (1380723-44-3) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613911359 DOI 10.1093/annonc/mdw374.18 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdw374.18 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 72 TITLE KEYNOTE-100: Phase 2 trial of pembrolizumab in patients with advanced recurrent ovarian cancer AUTHOR NAMES Matulonis U.A. Chen M. Puhlmann M. Shentu Y. Ledermann J. AUTHOR ADDRESSES (Matulonis U.A.) Medical Oncology, Dana-Farber Cancer Institute, Boston, United States. (Chen M.; Puhlmann M.; Shentu Y.) Medical Oncology, Merck and Co., Inc., Kenilworth, United States. (Ledermann J.) Oncology, University College London Hospitals, London, United Kingdom. CORRESPONDENCE ADDRESS U.A. Matulonis, Medical Oncology, Dana-Farber Cancer Institute, Boston, United States. SOURCE Annals of Oncology (2016) 27 Supplement 6. Date of Publication: 2016 CONFERENCE NAME 41st European Society for Medical Oncology Congress, ESMO 2016 CONFERENCE LOCATION Copenhagen, Denmark CONFERENCE DATE 2016-10-07 to 2016-10-11 ISSN 1569-8041 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Ovarian cancer is the most lethal gynecologic cancer, with approximately 80% of patients experiencing disease recurrence following standard front-line therapy. Currently, no curative therapy is available for recurrent ovarian cancer (ROC), which is an area with high unmet medical need. Pembrolizumab is a programmed death 1 (PD-1) inhibitor designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and, ultimately, immune rejection. Prior study of pembrolizumab in advanced epithelial ovarian cancer showed promising clinical activity. Here, we further evaluate the efficacy and safety of pembrolizumab in patients ( pts) with advanced ROC in the open-label, single-arm, 2-cohort KEYNOTE-100 study (NCT02674061). Trial design: Pts who are ≥18 years old with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and confirmed disease recurrence following front-line platinum-based therapy can be enrolled. Cohort A will include approximately 250 pts who received ≤2 prior therapies for ROC and had a platinum-free interval (PFI) or treatment-free interval (TFI) of ≥3 to 12 mo based on the last regimen received. Cohort B will include approximately 75 pts who received 3-5 prior therapies for ROC and had a PFI or TFI of ≥3 mo based on the last regimen received. Pts must also have measurable disease and ECOG performance status of 0-1 at baseline and must provide a tumor sample for PD-L1 analysis. Pts will be treated with pembrolizumab 200 mg every 3 wk for 35 cycles or until disease progression, death, unacceptable toxicity, or withdrawal of consent. Pts will have regular imaging and safety assessments during the study. The primary study objectives are to evaluate objective response rate per RECIST v1.1 (primary end point) in cohort A and cohort B all-comer populations and in tumor PD-L1 high-expression populations. Duration of response, progression-free survival, overall survival, and safety will also be evaluated. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS endogenous compound platinum programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female ovary carcinoma EMTREE MEDICAL INDEX TERMS adult cancer epidemiology clinical trial comparative effectiveness controlled clinical trial controlled study death disease duration drug therapy drug withdrawal gene expression human imaging lymphocyte major clinical study overall survival peritoneum cancer pharmacokinetics phase 2 clinical trial progression free survival recurrent disease response evaluation criteria in solid tumors risk assessment study design toxicity tumor regression uterine tube carcinoma young adult CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613911692 DOI 10.1093/annonc/mdw374.47 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdw374.47 COPYRIGHT Copyright 2017 Elsevier B.V., All rights reserved. RECORD 73 TITLE Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune diseases: A systematic review of case reports AUTHOR NAMES Abdel-Wahab N. Shah M. Suarez-Almazor M. AUTHOR ADDRESSES (Abdel-Wahab N.; Shah M.; Suarez-Almazor M.) Department of General Internal Medicine, University of Texas, MD Anderson Cancer Center, Houston, United States. (Abdel-Wahab N.) Rheumatology and Rehabilitation Department, Assiut University Hospitals, Houston, United States. CORRESPONDENCE ADDRESS N. Abdel-Wahab, Department of General Internal Medicine, University of Texas, MD Anderson Cancer Center, Houston, United States. SOURCE Arthritis and Rheumatology (2016) 68 Supplement 10 (1683-1684). Date of Publication: 1 Oct 2016 CONFERENCE NAME American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting, ACR/ARHP 2016 CONFERENCE LOCATION Washington, DC, United States CONFERENCE DATE 2016-11-11 to 2016-11-16 ISSN 2326-5205 BOOK PUBLISHER John Wiley and Sons Inc. ABSTRACT Background/Purpose: A systematic review of case reports to summarize the existing evidence on the use of checkpoint inhibitors in patients with cancer and preexisting autoimmune diseases. Methods: We searched Medline, EMBASE, Web of Science, PubMed ePubs, and the Cochrane Central Register of Controlled Trials (CENTRAL) through January 2016 with no restrictions. References cited in the included articles were searched manually. We included case reports describing patients with cancer and autoimmune disease diagnosed before starting treatment with the checkpoint inhibitors. We extracted data on patient's characteristics, type of checkpoint inhibitors, reported immune related adverse events (irAEs), how they were managed, and their clinical outcome, if discontinuation of immunotherapy was required, and if treatment rechallenge was reported. Results: Fourteen publications met inclusion criteria, reporting on 45 cases. Age of the cases ranged from 30 to 80 years; 25 patients (55.6%) were male. Forty three cases (95.6%) had melanoma. Preexisting autoimmune diseases included autoimmune thyroid diseases, rheumatoid arthritis, ulcerative colitis, psoriasis (two with psoriatic arthritis), multiple sclerosis, Crohn's disease, sarcoidosis, systemic lupus, Behcet disease, inflammatory arthritis, reactive arthritis, rheumatic fever, Sjogren's syndrome, transverse myelitis, and celiac disease. Of the 45 cases, 86.8% received concomitant treatment (corticosteroids, DMARDs, and biologics) for their autoimmune disease; 53.9% were still active at the time of immune checkpoint inhibitor therapy. Most received ipilimumab (88.9%). After immunotherapy: 1) 40.0% reported de novo irAEs, 2) 28.9% reported exacerbation of the preexisting autoimmune disease, 3) 8.9% reported both, and 4) 40.0% did not report any adverse events. Hypophysitis and colitis occurred in most cases (27.8% each) with de novo irAEs. Autoimmune thyroiditis, diabetes, glaucoma, interstitial nephritis, skin itching, and toxic epidermal necrolysis were also reported. Those with exacerbation of the preexisting autoimmune disease, had manifestations similar to those occurring before checkpoint therapy, and none developed new disease features. Patients were treated with corticosteroids and hormonal replacement therapy. Therapy with azathioprine, sulfasalazine, or infliximab was also reported. Discontinuation of immunotherapy was recommended in 33.3%, and resolution of irAEs was achieved in the majority of cases. Death was reported in one case with toxic epidermal necrolysis and in another with severe colitis. Treatment rechallenge was reported in a patient with ulcerative colitis who developed exacerbation of his colitis after initial use of ipilimumab. Upon rechallenge, he reported grade III anterior panhypopitutarism and tracheobronchitis. In a patient with pulmonary sarcoidosis, ipilimumab rechallenge was not associated with significant clinical symptoms. Conclusion: Forty percent of the cases did not experience irAE or disease exacerbation, despite many having active autoimmune disease at the time of checkpoint inhibition. Further studies are needed to establish the risk-benefit profile of this novel therapy in this population. EMTREE DRUG INDEX TERMS azathioprine corticosteroid disease modifying antirheumatic drug infliximab ipilimumab salazosulfapyridine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune thyroiditis melanoma EMTREE MEDICAL INDEX TERMS adverse drug reaction Behcet disease celiac disease clinical outcome Cochrane Library Crohn disease death diabetes mellitus diagnosis disease exacerbation drug therapy Embase female glaucoma human hypophysitis immunotherapy interstitial nephritis lung sarcoidosis male Medline multiple sclerosis myelitis pruritus psoriatic arthritis publication reactive arthritis rheumatic fever side effect Sjoegren syndrome substitution therapy symptom systematic review systemic lupus erythematosus toxic epidermal necrolysis tracheobronchitis ulcerative colitis Web of Science CAS REGISTRY NUMBERS azathioprine (446-86-6) infliximab (170277-31-3) ipilimumab (477202-00-9) salazosulfapyridine (599-79-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613888941 DOI 10.1002/art.39977 FULL TEXT LINK http://dx.doi.org/10.1002/art.39977 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 74 TITLE Ipilimumab and pembrolizumab induced thyroiditis AUTHOR NAMES Somasundaram A. Ukrainski M. Ahmed I. Fallon J.J. AUTHOR ADDRESSES (Somasundaram A.; Ukrainski M.; Ahmed I.) Thomas Jefferson University Hospital, Philadelphia, United States. (Fallon J.J.) Inspira Medical Center, Woodbury, Marlton, United States. CORRESPONDENCE ADDRESS A. Somasundaram, Thomas Jefferson University Hospital, Philadelphia, United States. SOURCE Endocrine Reviews (2015) 36 Supplement 2. Date of Publication: 2015 CONFERENCE NAME 97th Annual Meeting and Expo of the Endocrine Society, ENDO 2015 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2015-03-05 to 2015-03-08 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: In patients with metastatic melanoma, Ipilimumab, an antibody blocking cytotoxic T-Lymphocyte antigen 4 (CTLA-4), and pembrolizumab, a programmed death-1 (PD-1) molecule inhibitor, increase immunologic rejection of the tumor by enhancing the immune response (1). However, these immune check point inhibitors also cause side effects described as “immune-related adverse events” (IRAEs). We describe a patient, who developed thyroiditis and pancreatitis following treatment with ipilimumab and pembrolizumab. Clinical case: 45 year old Caucasian female with a history of stage III melanoma of scalp and hypertriglyceridemia presented to ED with abdominal pain, intractable nausea, vomiting, and watery diarrhea over 2 weeks. In addition, review of symptoms was significant for fatigue, decreased oral intake, and 16 lb weight loss. Despite wide excision of her scalp lesion, her melanoma recurred and she underwent treatment with chemotherapy, including 3 out of 4 cycles of ipilimumab and subsequently 5 cycles of pembrolizumab. Her last infusion of pembrolizumab was a week prior to her presentation. She was taking fenofibrate 135 mg daily. On exam, her BMI was 25.4, BP was 106/51 and HR was 103/min. She had multiple scalp lesions. There was no thyroid enlargement or tenderness and no hand tremors. Labs revealed ESR of 52 (0-20 mm/h), CRP 12.9 (0-0.9 mg/L) bicarbonate of 15 (24-32 mEq/L), ALP of 131 (38-126 U/L), AST of 64 (14-36 U/L), triglycerides of 168 (10-150 mg/dL), lipase of 1880 (23-300 U/L). TSH was 0.015 (0.465 4.68 mIU/L) with free T4 of 3.81 (0.78 - 2.19ng/dL), free T3 of 8.9 (2.77 -5.27 pg/mL). Thyroperoxidase antibodies was 4.7 (0-9 IU/cc), thyroglobulin antibodies was <0.9 (0-4 IU/cc) TSI was 105 % (<125 %). Thyroid ultrasound revealed normal texture gland. Patient was admitted and received intravenous fluids. CT of abdomen and pelvis demonstrated mild thickening of right colon wall. PET scan showed mild increased uptake in right thyroid and pancreas. Based on her clinical symptoms, lab and imaging results, a diagnosis of thyroiditis and pancreatitis was made, presumably autoimmune response to her chemotherapy. She was started on methylprednisolone intravenously, with significant clinical improvement. She was discharged on metoprolol and prednisone taper. Conclusion: Though rare, thyroiditis has been described as a side effect of anti-cancer immunotherapy. Polymorphism in CTLA4 gene confers increased susceptibility to variety of autoimmune thyroid disorders (2). Exact mechanism of IRAEs from pembrolizumab still remains to be elucidated; however, they are inflammatory in nature and may represent a breakdown of tolerance to self-antigens. Monitoring of thyroid and pituitary function at baseline and before each cycle is required, and medication discontinuation may be required. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab pembrolizumab EMTREE DRUG INDEX TERMS bicarbonate cytotoxic T lymphocyte antigen 4 endogenous compound fenofibrate methylprednisolone metoprolol prednisone thyroglobulin antibody thyroid peroxidase thyrotropin triacylglycerol triacylglycerol lipase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune thyroiditis EMTREE MEDICAL INDEX TERMS abdominal pain adult body mass body weight loss cancer immunotherapy case report Caucasian chemotherapy colon diagnosis diarrhea fatigue female free liothyronine index free thyroxine index gene mutation genetic predisposition goiter hand tremor human hypertriglyceridemia hypophysis function imaging infusion liquid melanoma middle aged monitoring nausea and vomiting pancreatitis pelvis positron emission tomography scalp symptom thyroid function ultrasound wide excision CAS REGISTRY NUMBERS bicarbonate (144-55-8, 71-52-3) fenofibrate (49562-28-9) ipilimumab (477202-00-9) methylprednisolone (6923-42-8, 83-43-2) metoprolol (37350-58-6) pembrolizumab (1374853-91-4) prednisone (53-03-2) thyrotropin (9002-71-5) triacylglycerol lipase (9001-62-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613817723 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 75 TITLE Ipilimumab induced hypophysitis may not affect all pituitary cell lines: A case study AUTHOR NAMES Kotwal A. Rao S. Haas R.A. AUTHOR ADDRESSES (Kotwal A.; Rao S.; Haas R.A.) University of Massachusetts Medical School, Worcester, United States. CORRESPONDENCE ADDRESS A. Kotwal, University of Massachusetts Medical School, Worcester, United States. SOURCE Endocrine Reviews (2015) 36 Supplement 2. Date of Publication: 2015 CONFERENCE NAME 97th Annual Meeting and Expo of the Endocrine Society, ENDO 2015 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2015-03-05 to 2015-03-08 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: Hypophysitis has emerged as an immune related adverse effect (IRAE) of anti-CTLA 4 antibodies like Ipilimumab, occurring in approximately 11% of cases with a higher predilection for males (1). Clinical case: A 68 year old gentleman presented to the Oncology clinic with headache, diplopia, fatigue, nausea, hot flashes and anorexia following the third cycle of 3mg/kg Ipilimumab for metastatic melanoma. He had a thyroidectomy for hyperthyroidism 40 years ago and was on Levothyroxine replacement. Before initiating Ipilimumab, thyroid function tests had been normal but adrenal function was not checked. Physical exam revealed proximal muscle weakness. Laboratory workup revealed low total Testosterone of 11 ng/dL (reference 241-827), low TSH of 0.09 uIU/mL (0.28-3.89), normal free T4 of 1.15 ng/dL (0.58-1.64) and normal electrolytes. Brain MRI showed new heterogeneous enhancement of the pituitary. Based on these findings, he was diagnosed with Ipilimumab induced hypophysitis (IH), and started on 90 mg Prednisone & testosterone gel. He also developed IRAEs of dermatitis and colitis, and did not receive further Ipilimumab therapy. On follow up MRI, the pituitary fullness resolved after three months. Prednisone was gradually tapered over five months but an attempt at discontinuation worsened the fatigue. He was then evaluated by Endocrinology and hormonal investigations revealed low AM Cortisol of 1.4 mcg/dL (reference 6.7-22.6), low ACTH of <5 pg/mL (ref <46), abnormal ACTH-stimulation test showing Cortisol response to 11.4 mcg/dL (≥18), low Prolactin of 0.6 ng/mL (2.6-13.3), low total Testosterone of <10 ng/dL, normal IGF-1 of 40 ng/dL (17-246) and inappropriately normal LH of 1.4 mIU/mL (1.2-8.6). Serum and urine osmolality as well as electrolytes were normal. He received Hydrocortisone replacement of 30 mg a day in divided doses, and Testosterone gel which he had stopped by himself was resumed. Fatigue was the only symptom that persisted and that too resolved after starting CPAP for his obstructive sleep apnea. Eight months after the diagnosis of IH, he remained asymptomatic on physiologic dose hydrocortisone and testosterone replacement. Conclusion: This case represents IH causing anterior hypopituitarism. An unusual feature is preserved Somatotroph function despite profound central hypoadrenalism and hypogonadism. The worsening of symptoms after discontinuation of steroids five months after presentation, and the improvement after reinitiating them, suggest that the hypopituitarism is permanent even though MRI findings resolve (2). A recent study implicated pituitary antibodies (3) as a possible method of detection in addition to MRI and hormone studies. There is not enough evidence to support the routine need for discontinuing Ipilimumab or the superiority of initial high dose versus physiologic steroid and hormone replacement in the management of IH (1). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticotropin electrolyte endogenous compound hormone hydrocortisone levothyroxine prednisone prolactin somatomedin C testosterone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cell line disease model growth hormone secreting cell hypophysitis EMTREE MEDICAL INDEX TERMS adrenal function adrenal insufficiency aged androgen therapy anorexia apnea monitoring brain case report colitis corticotropin test dermatitis diagnosis diplopia endocrinology follow up free thyroxine index headache hormone substitution hospital hot flush human human tissue hyperthyroidism hypogonadism hypopituitarism male metastatic melanoma muscle weakness nausea nuclear magnetic resonance imaging oncology sleep disordered breathing symptom thyroid function test thyroidectomy urine osmolality CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) levothyroxine (51-48-9) prednisone (53-03-2) prolactin (12585-34-1, 50647-00-2, 9002-62-4) somatomedin C (67763-96-6) testosterone (58-22-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613816568 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 76 TITLE Ipilimumab-induced hypophysitis-recurrence of symptoms during the course of steroid treatment AUTHOR NAMES Hanseree P. Poehls J.L. AUTHOR ADDRESSES (Hanseree P.) University of Wisconsin Hospital and Clinics, Madison, United States. (Poehls J.L.) University of Wisconsin, Madison, United States. CORRESPONDENCE ADDRESS P. Hanseree, University of Wisconsin Hospital and Clinics, Madison, United States. SOURCE Endocrine Reviews (2015) 36 Supplement 2. Date of Publication: 2015 CONFERENCE NAME 97th Annual Meeting and Expo of the Endocrine Society, ENDO 2015 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2015-03-05 to 2015-03-08 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 that was approved by FDA as monotherapy for metastatic melanoma in March 2011. There have been reports of immune-related adverse events affecting different organs. The most common endocrinopathy is hypophysitis with the incidence of 1.8-17%(1). Clinical case: 53 year old female with history of resected metastatic melanoma (N2b) of unknown primary site diagnosed by right inguinal lymph node biopsy. She entered a clinical trial and was randomized to ipilimumab therapy. After completing her fourth course of ipilimumab, she presented with headache that had progressively worsened over 2 weeks. She also noted fatigue, dizziness, and weight gain. She denied nausea, vomiting, visual symptoms, polydipsia or polyuria. Labs showed low TSH 0.23 uIU/mL(0.36-4.20 uIU/mL), low free T4 0.44 ng/dL(0.70-1.45 ng/dL), low free T3 2.0 pg/mL(2.2-4.0 pg/mL), low 8AM cortisol 3.3 mcg/dL(4.3-22.4 mcg/dL) with inappropriately normal ACTH 22 pg/mL(7-45 pg/mL). Electrolytes were normal. MRI of the brain demonstrated diffuse enlargement of the pituitary gland measuring 1.2 cm with mass effect on the optic chiasm and thickening of the pituitary infundibulum, suggestive of hypophysitis. Visual field exam was normal. Patient received high dose methylprednisolone infusions, about 2mg/kg on day 1, and about 1mg/kg on day 2 and 3. Levothyroxine 50 mcg daily was also started. Headache resolved 2 days after starting treatment and patient was discharged home with tapering course of prednisone. Headache recurred during the 4th week as she was tapered to replacement dose of hydrocortisone. Repeat MRI at that time showed pituitary gland had decreased to 1 cm with minimal residual inflammation. Hydrocortisone was changed back to prednisone 20 mg daily for 3 days and headache improved. Repeat TSH and free T4 were normal. When prednisone taper tried again, the patient had recurrent headache. Repeat MRI 8 weeks after initial presentation showed decrease in the size of pituitary now measuring 6 mm. Patient was continued on prednisone 20 mg daily with plans to taper in 1-2 weeks if/when headache resolves. Clinical Lessons: The recommended treatment for immune-related adverse events secondary to ipilimumab, including hypophysitis, is high-dose glucocorticoids tapered down gradually over 1 month to replacement doses. Ipilimumab should be held as well. Most patients respond well to this treatment with resolution of symptoms within a few days. This report is to remind physicians to monitor for recurrence of symptoms while tapering steroids as some patients may require a longer tapering course. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) hydrocortisone ipilimumab EMTREE DRUG INDEX TERMS corticotropin electrolyte endogenous compound levothyroxine methylprednisolone prednisone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) disease duration hypophysitis relapse symptom EMTREE MEDICAL INDEX TERMS adult adverse drug reaction body weight gain case report controlled clinical trial controlled study diagnosis dizziness drug megadose drug therapy fatigue female free liothyronine index free thyroxine index headache human infusion inguinal lymph node low drug dose lymph node biopsy metastatic melanoma middle aged nausea and vomiting nuclear magnetic resonance imaging optic chiasm physician pituitary stalk polydipsia polyuria randomized controlled trial side effect visual field CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) levothyroxine (51-48-9) methylprednisolone (6923-42-8, 83-43-2) prednisone (53-03-2) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613816511 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 77 TITLE The growing concern for autoimmune hypophysitis due to ipilimumab AUTHOR NAMES Denman D. Mongelluzzo G.J. Lock J.H. Panikkar R. Zeng Y. Gingrich P. Hu Y. AUTHOR ADDRESSES (Denman D.; Mongelluzzo G.J.; Lock J.H.; Panikkar R.; Zeng Y.; Gingrich P.; Hu Y.) Geisinger Medical Center, Danville, United States. CORRESPONDENCE ADDRESS D. Denman, Geisinger Medical Center, Danville, United States. SOURCE Endocrine Reviews (2015) 36 Supplement 2. Date of Publication: 2015 CONFERENCE NAME 97th Annual Meeting and Expo of the Endocrine Society, ENDO 2015 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2015-03-05 to 2015-03-08 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Ipilimumab (IP), a human antibody against cytotoxic T-lymphocyte antigen 4 (anti-CTLA4), is FDA approved for the treatment of unresectable or metastatic malignant melanoma. Here we report two cases of patients treated with IP who developed hypopituitarism from autoimmune hypophysitis (AIH). Case reports: Case 1 is a 52 year old male with stage IIIb malignant melanoma of perianal skin who was enrolled in a “phase III randomized study of adjuvant IP therapy versus high-dose Interferon α-2b for resected high-risk melanoma”. After receiving four doses of IP (10 mg/kg), the patient presented with a severe headache and extreme fatigue. Lab work revealed total testosterone 32.71 (193 - 740 ng/dL), TSH 0.17 (0.27 - 4.2 uIU/mL), free T4 0.40 (0.7 - 1.7 ng/dL), and cortisol 3.1 (6.2-19.4 ug/dL). MRI showed a diffusely enlarged pituitary gland and infundibulum with homogenous enhancement. Hypopituitarism due to AIH induced by IP was suspected. IP was stopped and he was treated with prednisone 60 mg for five days followed by hydrocortisone, levothyroxine, and androgen replacement. His symptoms were resolved rapidly. At two months follow up, an MRI showed complete resolution of enlarged pituitary; lab results did not show signs of pituitary function recovery. Case 2 is a 56 year old female with stage IIIc metastatic melanoma of her left back who was enrolled in the same trial to receive IP (3 mg/kg). After three doses of IP, she developed headache and mild fatigue. Labs showed TSH 0.15 (0.27 - 4.2 uIU/mL), free T4 0.54 (0.7 - 1.7 ng/dL), cortisol 0.7 (6.2-19.4 ug/dL), and ACTH 5.9 (0-16 pg/ml). MRI showed a diffusely enlarged pituitary gland consistent with hypophysitis. IP was stopped and she was treated with prednisone 60 mg for five days, followed by levothyroxine and hydrocortisone replacement. Her symptoms improved shortly after. At one month follow up, an MRI showed improvement of pituitary size, but lab results did not show signs of pituitary function recovery. Discussion: Both patients developed hypopituitarism due to presumed AIH secondary to IP therapy. AIH is a rare endocrine disease, which has been reported in about 4% of patients involved in IP trials. Most patients developed AIH after receiving the third dose of treatment, which is similar to the cases reported here. Both cases presented with headache and fatigue. Treatments have corrected their clinical symptoms and radiographic abnormalities. However we haven't seen the recovery of endogenous pituitary function several months after the events. The mechanism of AIH induced by IP likely is related to its immunostimulation effect. Whether large dose of steroids have helped their recovery process or not is unknown. Conclusion: AIH is a rare but significant complication from IP treatment. Endocrinologists and Oncologists need to be aware of this, as it can cause hypopituitarism, which could be life threatening if unrecognized. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS adjuvant alpha2a interferon corticotropin endogenous compound hydrocortisone levothyroxine prednisone testosterone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune hypophysitis EMTREE MEDICAL INDEX TERMS adult adverse drug reaction androgen therapy cancer susceptibility case report clinical trial congenital malformation controlled clinical trial controlled study drug megadose drug therapy endocrinologist fatigue female follow up free thyroxine index headache human hypophysis function hypopituitarism immunostimulation male metastatic melanoma middle aged nuclear magnetic resonance imaging oncologist randomized controlled trial remission side effect skin symptom CAS REGISTRY NUMBERS alpha2a interferon (76543-88-9) corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) levothyroxine (51-48-9) prednisone (53-03-2) testosterone (58-22-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613816491 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 78 TITLE Treatment of ipilimumab induced graves ' disease in a patient with metastatic melanoma AUTHOR NAMES Azmat U. Liebner D. Joehlin-Price A. Agrawal A. Nabhan F. AUTHOR ADDRESSES (Azmat U.; Liebner D.; Joehlin-Price A.; Agrawal A.; Nabhan F.) Ohio State University, Columbus, United States. CORRESPONDENCE ADDRESS U. Azmat, Ohio State University, Columbus, United States. SOURCE Endocrine Reviews (2015) 36 Supplement 2. Date of Publication: 2015 CONFERENCE NAME 97th Annual Meeting and Expo of the Endocrine Society, ENDO 2015 CONFERENCE LOCATION San Diego, CA, United States CONFERENCE DATE 2015-03-05 to 2015-03-08 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a receptor that down regulates T cell signaling and proliferation. This can lead to tolerance of tumor-associated antigens. Ipilimumab is a human monoclonal antibody directed against CTLA-4 and by blocking it this can enhance the anti-tumor effects of T cells. However, due to this mechanism it can also cause decreased immune self-tolerance and hence immune-related adverse events such as endocrinopathies. The most common reported endocrinopathy is hypophysitits with an incidence of 8%, followed by hypothyroidism and thyroiditis at 6%. Graves' disease occurs more rarely without a clear rate in the literature. Clinical Case: We present a 67 year old male with metastatic melanoma involving cervical lymph nodes and lungs, who had normal thyroid function tests prior to starting ipilimumab at a dose of 3 mg/kg every 3 weeks. After 2 cycles, he developed clinical and biochemical hyperthyroidism. The picture was consistent with Graves' disease evident by elevated thyroid stimulation immunoglobulin and homogenous increased I-123 thyroid uptake. Ipilimumab was held, and he was started on methimazole. Restaging CT scans showed persistent cervical adenopathy, but resolution of his lung nodules consistent with a response to ipilimumab. Once his hyperthyroidism was controlled on methimazole, he received two additional cycles of ipilimumab. Methimazole was continued during this time and hyperthyroidism remained controlled. He then underwent a left radical neck dissection for residual metastatic melanoma limited to the neck along with total thyroidectomy. The decision to perform total thyroidectomy as a definitive treatment of hyperthyroidism in this patient was influenced by the fact that he was undergoing neck surgery for melanoma; the left thyroid lobe was in close proximity to the melanoma lymph nodes, potential need for future therapy with ipilimumab, and patient preference. Pathology revealed nodular and papillary hyperplasia of the thyroid, consistent with Graves' disease, with incidental papillary thyroid micro carcinoma. Conclusion: Our case is the first patient that we are aware of who was treated with total thyroidectomy for Graves' disease that he developed after starting ipilimumab. Graves' disease is rare, with the most common thyroid adverse events being subclinical/mild hypothyroidism and thyroiditis associated with ipilimumab. Although ipilimumab has not been noted to worsen pre-existing thyroid disease, it is possible that our patient may have had preexisting thyroid non-clinical disease that became apparent after starting ipilimumab. No specific guidelines exist for the management of Graves' disease in this setting or concerning the use of ipilimumab in patients being treated with methimazole. In our case the patient was successfully treated with methimazole, continuation of ipilimumab, and total thyroidectomy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS endogenous compound immunoglobulin iodine 123 thiamazole EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) Graves disease metastatic melanoma EMTREE MEDICAL INDEX TERMS adverse drug reaction aged carcinoma case report cervical lymph node cervical lymphadenopathy clinical trial computer assisted tomography consensus development drug therapy human hypothyroidism immunological tolerance lung nodule male neck dissection pathology patient preference side effect surgery thyroid function test thyroid hyperplasia thyroidectomy thyroiditis CAS REGISTRY NUMBERS immunoglobulin (9007-83-4) iodine 123 (15715-08-9) ipilimumab (477202-00-9) thiamazole (60-56-0) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613818153 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 79 TITLE Novel immunomodulating therapy ipilimumab induced acute adrenal insufficiency secondary to autoimmune hypophysitis in a patient with squamous cell lung carcinoma AUTHOR NAMES Chon D. Robertson A.M. Bhat S. AUTHOR ADDRESSES (Chon D.) UCLA Health Los Angeles, United States. (Robertson A.M.) University of California, Los Angeles, Manhattan Beach, United States. (Bhat S.) David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare Systems, Los Angeles, United States. CORRESPONDENCE ADDRESS D. Chon, UCLA Health Los Angeles, United States. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction Ipilimumab (IP) is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 that is FDA approved for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as lung carcinomas. IP induces severe immune-related adverse events (irAEs) and endocrine irAEs are among the least recognized but among the highly symptomatic to occur. Before anti-CTLA4 therapy, autoimmune hypophysitis (AIH) was a rare disease confined primarily to postpartum women. AIH has emerged as a distinctive side effect of CTLA4-blocking antibodies. The median time to onset is 4 months after initiating treatment with IP, and symptomatic secondary adrenal insufficiency occurred in 84% of patient with hypophysitis in one series 1. We describe a case of hypophysitis presenting with acute adrenal insufficiency after his 4th dose of IP. Clinical Case A 60 year old male with a history of metastatic squamous cell lung carcinoma and prior history of hypothyroidism who was enrolled in an investigational cancer immunotherapy trial with adjuvant IP presented to the hospital with three weeks of fever, fatigue, poor appetite, weight loss, and nausea since his last treatment. On presentation to the Emergency Department, his initial vitals signs were significant for a temperature of 38.2 degrees C, heart rate of 121, and blood pressure of 77/55 mmHg. Physical exam was notable for moist skin and tachycardia. Initial laboratory studies showed ACTH level of 4.2 pg/ml (6-59), an 8am cortisol level of 4.5 ug/dl (8-25). A cortisol one hour after cosyntropin stimulation was 4.0 ug/dl. TSH 2.45 mcIU/ml (0.3-4.7) free T4 1.5 ng/dl (0.8-1.6), total testosterone 359 ng/dl and normal electrolytes. MRI showed a diffusely enlarged pituitary gland consistent with hypophysitis. Adrenal insufficiency secondary to AIH induced by IP was suspected. He was started on stress doses of hydrocortisone and showed a rapid clinical response. At two months follow up he remained on steroids and did not show signs of pituitary function recovery. Conclusion This case illustrates the potential for secondary adrenal insufficiency caused by AIH with the use of IP. The mechanism of AIH induced by IP is heightened autoimmunity which leads to the endocrinopathies. The clinical presentation of hypophysitis is often non-specific and may overlap with cancer-related constitutional symptoms, and adrenal insufficiency may not immediately be recognized but may be life threatening. Current literature recommends high dose steroids for IP induced irAes, tapered down to replacement doses over 1 month. Measurements of pituitary autoantigens, which are presently not clinically available, may improve our ability to diagnose hypophysitis 1. Validating predictive factors of autoimmune toxicity are urgently needed. This case emphasizes the need for early recognition of secondary adrenal insufficiency with the use of IP. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS adjuvant autoantigen blocking antibody corticotropin cytotoxic T lymphocyte antigen 4 electrolyte endogenous compound hydrocortisone testosterone tetracosactide thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency autoimmune hypophysitis squamous cell lung carcinoma EMTREE MEDICAL INDEX TERMS adult autoimmunity blood pressure body weight loss cancer immunotherapy case report chemical stress diagnosis emergency ward fatigue fever follow up free thyroxine index heart rate human hypophysis function hypothyroidism loss of appetite male middle aged nausea nuclear magnetic resonance imaging recognition skin symptom tachycardia toxicity CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) ipilimumab (477202-00-9) testosterone (58-22-0) tetracosactide (16960-16-0) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613523573 DOI 10.1210/endo-meetings.2016.NP.13.FRI-554 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.NP.13.FRI-554 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 80 TITLE Ipilimumab induced hypophysitis-an emerging poly-endocrinopathy AUTHOR NAMES McAdams B.H. AUTHOR ADDRESSES (McAdams B.H.) University of South Carolina, Palmetto Health Richland, Columbia, United States. CORRESPONDENCE ADDRESS B.H. McAdams, University of South Carolina, Palmetto Health Richland, Columbia, United States. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Title: Ipilimumab Induced Hypophysitis - An Emerging Poly-endocrinopathy Introduction: Ipilimumab (Yervoy) is a novel cytotoxic T-lymphocyte antigen-4 (CTLA4)- blocking antibody, first approved March 2011 for the therapeutic use of metastatic melanoma. Although extremely rare, cases of immune-mediated endocrinopathies have surfaced in the last four years. Clinical Case: The spectrum of Ipilimumab induced autoimmune endocrine disease includes hypophysitis, primary hypothyroidism, and primary adrenal insufficiency; usually occurring several weeks following initiation of therapy, suggesting a possible cumulative effect. Our objective is to describe four recent cases of Ipilimumab induced hypophysitis at our institution; including the clinical presentation and therapeutic measures taken. While the precise mechanism of injury to the endocrine system is not fully understood; it is certain that if this condition is not promptly recognized it can be life threatening. Conclusion: Given the increasing use of immune checkpoint inhibitors, it is important for all physicians; including generalists, ER physicians, oncologists, and endocrinologists to be aware of this emerging poly-endocrinopathy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) Addison disease hypophysitis EMTREE MEDICAL INDEX TERMS case report endocrine disease endocrinologist human hypothyroidism injury oncologist CAS REGISTRY NUMBERS ipilimumab (477202-00-9) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613523947 DOI 10.1210/endo-meetings.2016.NP.13.FRI-569 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.NP.13.FRI-569 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 81 TITLE Ipilimumab-induced hypophysitis AUTHOR NAMES Telford R. Patel A.J. Roberson G. Bag A. AUTHOR ADDRESSES (Telford R.; Patel A.J.; Roberson G.; Bag A.) University of Alabama at Birmingham, Birmingham, United States. CORRESPONDENCE ADDRESS R. Telford, University of Alabama at Birmingham, Birmingham, United States. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction/Learning Objectives: 1. Familiarizing physicians about a very important, potentially life-threatening side effect of Ipilimumab, most commonly used drug for treatment of unresectable melanoma patients: Ipilimumab-induced hyophysitis (IIH). 2. Discussing the “red-flags” symptoms and radiological and laboratory manifestations to diagnose IIH. Case Presentation: Approximately 1 year after surgical resection of acral lentiginous melanoma of the left heel, a 73-year-old female patient presented with extensive metastasis to the lung and supraclavicular lymph nodes. Imaging of the CNS during staging did not reveal any intracranial metastasis. She was treated with Yervoy (Ipilimumab). Three weeks after her 2ndcycle of Ipilimumab, she presented with severe headache and clumsiness of her right leg. Brain metastasis was suspected, and a brain MRI was performed that demonstrated three new brain metastases as well as enlargement and hyperenhancement of the pituitary gland. Her laboratory investigation demonstrated hyponatremia with a serum sodium of 112 mMol/L (normal range:133-145), low TSH (0.329 mcIU/mL; normal range:0.350-5.500) low free thyroxine (0.68 ng/dL; normal range: 0.62-1.57). She was treated with levothyroxine and glucocorticoid replacement. A repeat head computed tomography (CT) after one month demonstrated a normal pituitary gland, and she became eunatremic. Discussion: Ipilimumab is an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody commonly used to treat metastatic melanoma. Autoimmune endocrine abnormalities including hypophysitis, adrenalitis, and thyroiditis are known side effects. Ipilimumab-induced hypophysitis (IIH) is relatively common in patients treated with Ipilimumab occurring in up to 11%, which is why it is important for physicians to become familiar with this life-threatening complication. IIH usually leads to permanent anterior hypopituitarism but is actually associated with a better mortality outcome in the setting of metastatic melanoma. IIH has been described as a type of autoimmune disorder, which is distinctly different from lymphocytic hypophysitis (LH). Imaging findings are usually enlargement and hyperenhancement affecting the pituitary stalk and adenohypophysis, which can be confused with a metastasis to the pituitary gland or sella. Imaging findings combined with clinical and laboratory findings can be used to confidently diagnose IIH and can avoid a potential biopsy procedure. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 cytotoxic T lymphocyte antigen 4 antibody endogenous compound glucocorticoid levothyroxine thyrotropin thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis EMTREE MEDICAL INDEX TERMS adenohypophysis adverse drug reaction aged autoimmune disease biopsy technique brain metastasis case report clinical trial computer assisted tomography diagnosis drug therapy female headache heel human human tissue hyponatremia hypopituitarism lung lymphocyte male metastatic melanoma mortality nuclear magnetic resonance imaging physician pituitary stalk side effect skull sodium blood level staging supraclavicular lymph node surgery thyroiditis CAS REGISTRY NUMBERS ipilimumab (477202-00-9) levothyroxine (51-48-9) thyrotropin (9002-71-5) thyroxine (7488-70-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613523666 DOI 10.1210/endo-meetings.2016.NP.13.FRI-559 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.NP.13.FRI-559 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 82 TITLE Transient thyrotoxicosis during nivolumab treatment AUTHOR NAMES Van Kooten M.J. Van Den Berg G. Glaudemans A.W.J.M. Hiltermann T.J.N. Groen H.J.M. Links T.P. AUTHOR ADDRESSES (Van Kooten M.J.; Hiltermann T.J.N.; Groen H.J.M.; Links T.P.) University of Groningen, University Medical Center Groningen, Groningen, Netherlands. (Van Den Berg G.) University Medical Center Groningen, Groningen, Netherlands. (Glaudemans A.W.J.M.) University of Groningen, University Medical Center Groningen, Netherlands. CORRESPONDENCE ADDRESS M.J. Van Kooten, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: Immune checkpoint-blocking antibody nivolumab is a promising new drug to treat different malignancies by promoting immune responses via blocking programmed death-1 ligands on tumor- and stromal-cells in peripheral tissues. Besides its benefits, nivolumab can have endocrine side effects like hypothyroidism (n=19, 7%), hyperthyroidism (n=4, 1%), and thyroiditis (n=1, <1%), mostly developing around week 12 after the start of therapy with nivolumab (1). The optimal treatment for this hyperthyroidism has thus as yet not been established. Clinical case: We report two cases with a thyrotoxicosis during nivolumab treatment. A 63-year-old female diagnosed with squamous-cell non-small-cell lung carcinoma (NSCLC) stage cT3N3M1b developed a thyrotoxicosis, including symptoms like progressive fatigue, excessive sweating, palpitations, and weight loss together with tachycardia and a nontender, enlarged, diffuse goiter, four weeks after initiation of treatment with nivolumab. Laboratory findings revealed FT4 47.5 pmol/L (11.0-19.5), FT3 10 pmol/L (4.4-6.7), TSH 0.020 mU/L (0.5- 4.0), and negative thyroid antibodies. Medical history was negative for thyroid disease. Second-degree relatives were known to have hyperthyroidism and goiter. (18)F-fluorodeoxyglucose positron emission tomography computed tomography (FDG PET/CT) performed at baseline and 6 weeks after starting nivolumab showed an intense symmetrically increased uptake in the thyroid not present at baseline. Levothyroxine was started eight weeks after start of nivolumab therapy when hypothyroidism occurred (FT4 7.2 pmol/l). A 71-year-old female, diagnosed with squamous-cell NSCLC stage T2aN2-3M1b presented with symptoms of thyrotoxicosis: excessive sweating and palpitations two weeks after initiation of treatment with nivolumab, and a diffuse enlarged and tender thyroid. Laboratory examination showed FT4 53.1 pmol/L, FT3 14.3 pmol/L, TSH 0.010 mU/L, and negative thyroid antibodies. Medical and family histories were negative for thyroid diseases. Six weeks after starting nivolumab a FDG-PET/CT scan showed symmetrical increased FDG uptake in the thyroid in comparison to baseline. Eight weeks after start of nivolumab therapy hypothyroidism developed (FT4 8.4 pmol/L), so levothyroxine was started. Conclusion: Both cases demonstrate that within 2-4 weeks treatment with nivolumab may provoke a transient thyrotoxicosis followed by a hypothyroidism. Temporary treatment with a beta blocker may be sufficient. We assume an immune-mediated destructive thyroiditis to be the underlying pathophysiological mechanism, based on the increased FDG uptake and the transient thyrotoxicosis followed by hypothyroidism. Since the number of patients treated with nivolumab is expected to increase, our case report should raise awareness of this endocrine side effect. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS beta adrenergic receptor blocking agent endogenous compound levothyroxine thyroid antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) thyrotoxicosis EMTREE MEDICAL INDEX TERMS adult adverse drug reaction aged awareness body weight loss clinical article clinical trial computer assisted emission tomography diagnosis drug therapy endocrine system family study fatigue female goiter heart palpitation human hyperhidrosis hypothyroidism laboratory test medical history middle aged non small cell lung cancer second-degree relative side effect squamous cell symptom tachycardia thyroiditis CAS REGISTRY NUMBERS levothyroxine (51-48-9) nivolumab (946414-94-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613521700 DOI 10.1210/endo-meetings.2016.THPTA.11.SUN-277 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.THPTA.11.SUN-277 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 83 TITLE Endocrine immune-related adverse events (irAEs) due to combination treatment with ipilimumab and nivolumab in patients with advanced stages of melanoma AUTHOR NAMES Adimoolam D. Inzucchi S.E. Sznol M. AUTHOR ADDRESSES (Adimoolam D.; Inzucchi S.E.) Yale School of Medicine, New Haven, United States. (Sznol M.) Yale School of Medicine, United States. CORRESPONDENCE ADDRESS D. Adimoolam, Yale School of Medicine, New Haven, United States. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Combination immune checkpoint blockade with ipilimumab (ipi), an antibody that blocks activation of cytoxic T-lymphocyte antigen 4 (CTLA-4), and nivolumab (nivo), an antibody to programmed cell death receptor 1 (PD-1), has led to longer progression-free survival in patients with advanced melanoma. There is also a growing number of endocrine immune-related adverse events (irAEs) related to these medications. There are few reports, however, about the frequency of endocrine irAEs in the setting of combination treatment. The goal of this study was to identify the incidence, clinical presentation, prognosis, and management of these irAEs. Methods: We performed a retrospective analysis of 25 patients who received combination ipilimumab and nivolumab therapy for metastatic melanoma at the Yale Cancer Center between 2009 and 2014. We analyzed each patient's clinical history, symptoms, laboratory testing, and imaging to describe each case of endocrine irAE. Results: 11 of 25 patients (44%) treated with combination ipi/nivo developed a significant endocrine irAE, with 5 of these 11 patients (45%) experiencing more than one. 20% (n=5) of the original cohort developed thyroiditis, 24% (n=6) developed primary hypothyroidism not associated with thyroiditis, and 12% (n=3) developed hypophysitis. The average time it took to develop an endocrine irAE was 6.4 months (range: 1 - 36 months). The majority of patients who developed thyroiditis did so within the first month of ipi/nivo therapy (mean: 1.4 months, range: 1 to 3 months). 4 of the 5 patients with thyroiditis progressed to primary hypothyroidism within 1 to 2 months (mean: 1.2 months). Hypophysitis tended to develop somewhat later (mean: 9 months, range: 2 - 21 months). Majority of endocrine irAEs were initially diagnosed based on symptoms (in 8 of 11 patients, 73%). The most common symptoms included fatigue and anergy (5 of 11 patients, 45%). The majority (3 of 5 patients, 60%) diagnosed with primary hypothyroidism following thyroiditis required long-term levothyroxine. There was no resolution of hypophysitis and all patients required long-term glucocorticoid therapy. Conclusions: There is limited literature identifying endocrine irAEs associated with combination ipi/nivo therapy. In comparison to the largest single center review of endocrine irAEs, we have found a similar trend in the frequency of irAEs with combined treatment (thyroid disease being the most common, followed by hypophysitis). However; our study has identified a higher percentage of endocrine irAEs of all types and provides an in-depth analysis of each patient's clinical history and progression. Because most patients in our study were identified after development of symptoms, our data suggests the potential role for routine screening (before and during treatment) of patients to identify those who may be at risk for developing symptomatic endocrine irAEs. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab nivolumab EMTREE DRUG INDEX TERMS glucocorticoid levothyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) endocrine system metastatic melanoma side effect EMTREE MEDICAL INDEX TERMS adverse drug reaction clinical article clinical trial controlled study diagnosis disease duration drug combination drug therapy fatigue human hypophysitis hypothyroidism imaging prognosis retrospective study screening symptom thyroiditis CAS REGISTRY NUMBERS ipilimumab (477202-00-9) levothyroxine (51-48-9) nivolumab (946414-94-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613521549 DOI 10.1210/endo-meetings.2016.TB.7.SUN-085 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.TB.7.SUN-085 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 84 TITLE Patterns of thyroid dysfunction in pembrolizumab-induced painless thyroiditis: High prevalence of subclinical disease AUTHOR NAMES Lam T. Burns K. Carlino M. Gunton J.E. Kong B. Park J. Kefford R.F. Chipps D.R. AUTHOR ADDRESSES (Lam T.; Burns K.; Carlino M.; Gunton J.E.; Kong B.; Park J.; Kefford R.F.; Chipps D.R.) Westmead Hospital, Sydney, Australia. CORRESPONDENCE ADDRESS T. Lam, Westmead Hospital, Sydney, Australia. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: New immune-modulatory therapies for malignancies such as melanoma have transformed their management with significantly enhanced survival outcomes. Pembrolizumab is an antibody against the programmed-death-1 (PD-1) molecule that increases the cytotoxic function of T-cells with excellent tumour response rates. Endocrinopathies including thyroiditis are an increasingly recognised side effect of this medication. However, the associated clinical patterns are yet to be fully elucidated. We describe the prevalence and characteristics of thyroiditis induced by pembrolizumab at a major melanoma treatment centre. Methods: A retrospective cohort study was performed in a population of patients with metastatic melanoma receiving pembrolizumab at a tertiary referral centre in Sydney. Hospital medical records and pathology databases were reviewed for thyroid function tests (TFTs). Inclusion criteria included patients who received at least two doses of pembrolizumab with two or more TFTs. Patients with pre-existing thyroid dysfunction were excluded. Where available, thyroid ultrasounds were also reviewed. Results: A cohort of 50 patients who had regular TFTs collected during the course of treatment with pembrolizumab as single agent were reviewed. The mean age was 62 ± 14 years. Thirty-three patients (66.0%) were male. Twelve patients (24.0%) developed TFT abnormalities on treatment. The median time to onset of thyroid dysfunction was 14 (range 3 to 97) weeks. The patterns of thyroid dysfunction included subclinical hypothyroidism (6/12, 50%) which was transient in four of six patients, clinical hypothyroidism without a preceding hyperthyroid phase (2/12, 16.7%), and clinical hypothyroidism with preceding subclinical or overt hyperthyroidism (4/12, 33.3%, TSH receptor antibodies not detected in four patients). None of the six patients who developed clinical hypothyroidism experienced thyroidal pain, and all had thyroiditis confirmed on ultrasound. Thyroid antibodies were present in only one of six patients with clinical hypothyroidism. Fine needle aspiration biopsy was performed in two patients with nodules on ultrasound which revealed lymphocytic thyroiditis with multinucleated giant cells. Thyroxine withdrawal was attempted in 2 patients (5 months and 17 months after diagnosis) but hypothyroidism persisted. Conclusion: Thyroid dysfunction is an increasingly recognised side effect of melanoma immunomodulatory therapy. Both clinical and subclinical hypothyroidism are common, and appear equally represented in our cohort. However, the exact pathogenesis of this condition still remains unclear. Given the significant variation in time of onset and rate of development of thyroid dysfunction, regular frequent testing of TFTs should be performed. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS thyroid antibody thyrotropin receptor antibody thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune thyroiditis hyperthyroidism prevalence EMTREE MEDICAL INDEX TERMS adult adverse drug reaction clinical article clinical trial cohort analysis congenital malformation controlled study data base diagnosis drug therapy drug withdrawal female fine needle aspiration biopsy giant cell human male medical record metastatic melanoma middle aged pain pathology side effect subclinical hypothyroidism tertiary care center thyroid function test ultrasound CAS REGISTRY NUMBERS pembrolizumab (1374853-91-4) thyroxine (7488-70-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613520225 DOI 10.1210/endo-meetings.2016.THPTA.2.SUN-249 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.THPTA.2.SUN-249 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 85 TITLE Silent (painless) thyroiditis induced by newest PD-1 inhibitor pembrolizumab AUTHOR NAMES Pena J.M.M. Kung J.T. AUTHOR ADDRESSES (Pena J.M.M.; Kung J.T.) Tufts Medical Center, Boston, United States. CORRESPONDENCE ADDRESS J.M.M. Pena, Tufts Medical Center, Boston, United States. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Backround: In recent years, significant progress has been made in cancer immunotherapy by the development of drugs acting as modulators of immune checkpoint proteins. Programmed death-1 (PD-1) inhibitors are highly selective anti-PD-1 humanized monoclonal antibody which reverse T-cell suppression and induce antitumor responses (1). As with all new medications, side effects start coming to light with increased use and time of follow up. Clinical Case: We present a case of Painless Thyroiditis induced by the newest PD-1 inhibitor, pembrolizumab. 83 year old F with diagnosis of adenocarcinoma of the lung stage IIIb who received first line and second line chemotherapy but unfortunately experienced side effects from these medications and the primary disease continued to progress. As an alternative resource she was initiated on the PD-1 inhibitor pembrolizumab. Baseline TSH was at normal limits and was rechecked three weeks after the first dose and prior considering the administration of a second dose. TSH decreased to 0.03 mIU/mL (0.465 4.68 mIU/L) with normal T3 and FT4. At five weeks TSH increased to 34.01 mIU/mL and FT4 was undetectable. Patient reported worsened fatigue and levothyroxine was initiated. At 8 weeks TSH decreased to 5.54 mIU/mL with normal FT4 and at 27 weeks TSH normalized at 2.32 mIU/mL. Thyroglobulin antibody >1000 U/mL (0.0 - 9.9 U/mL), TPO microsomal antibody 344.8 U/mL (0.0 - 5.9 U/mL). Discussion: In a RCT (2) comparing pembrolizumab and ipilimubab for the treatment of melanoma, thyroid dysfunction was the most common side effect. Pembrolizumab had the higher rate of adverse effects between the two with hypothyroidism reported in 10.1% in the 2- week group and 8.7% in the 3-week group and hyperthyroidism in 6.5% and 3.2% respectively. An observational study (4) for melanoma treatment with nivolumab for up to 96 weeks reported a 5.6% incidence rate of hypothyroidism. Case series (3) with exposure to PD-1 inhibitors have reported an initial thyrotoxic phase starting 3-6 weeks after the first immunotherapy dose, similar to our patient. All patients had elevated thyroglobulin and TPO antibodies. The mechanism of thyroiditis may be related to breaking of immune self-tolerance but it is unclear at this point. Conclusions: We must recognize these novel immunotherapies have the potential to cause selective immunotoxic effects on the thyroid gland and several other endocrine organs and the long term side effects remain to be found. Pembrolizumab, the newer and most promising PD- 1 inhibitor, appears to carry the highest risk for thyroid dysfunction and the manufacturer recommends checking TSH every 3 weeks with the infusion. For nivolumab the manufacturer recommends checking every 6 weeks. Anticipation and low threshold are key for diagnosis and control of the complications can be achieved without difficulties thus allowing drug continuation. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab programmed death 1 receptor EMTREE DRUG INDEX TERMS endogenous compound levothyroxine microsome antibody nivolumab thyroglobulin thyroglobulin antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) thyroiditis EMTREE MEDICAL INDEX TERMS aged case report case study chemotherapy diagnosis endocrine gland exposure fatigue female human hyperthyroidism hypothyroidism immunological tolerance immunotherapy immunotoxicity incidence infusion lung adenocarcinoma melanoma observational study thyrotoxicosis very elderly CAS REGISTRY NUMBERS levothyroxine (51-48-9) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) thyroglobulin (9010-34-8) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613521543 DOI 10.1210/endo-meetings.2016.THPTA.9.FRI-284 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.THPTA.9.FRI-284 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 86 TITLE Incidence of thyroid immune-related adverse events in melanoma patients treated with pembrolizumab in an expanded access program AUTHOR NAMES De Filette J. Jansen Y. Schreuer M. Bravenboer B. Neyns B. Velkeniers B. AUTHOR ADDRESSES (De Filette J.) UZ Brussel, Brussels, Belgium. (Jansen Y.; Schreuer M.; Bravenboer B.; Neyns B.; Velkeniers B.) UZ Brussel, Brussel, Belgium. CORRESPONDENCE ADDRESS J. De Filette, UZ Brussel, Brussels, Belgium. SOURCE Endocrine Reviews (2016) 37:2 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 98th Annual Meeting and Expo of the Endocrine Society, ENDO 2016 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2016-04-01 to 2016-04-04 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Pembrolizumab, a humanized IgG4 monoclonal antibody (mAb) that blocks the programmed cell death protein 1 receptor (PD-1) is registered for treatment of patients (pts) with unresectable advanced melanoma. Immune-checkpoint inhibiting mAb are associated with a risk for immune-related adverse events (irAE) that can affect the endocrine organs. We retrospectively reviewed the electronic medical records of 77 melanoma pts who initiated treatment with pembrolizumab (2mg/kg every 3 weeks) in an expanded access program between September 2014 and October 2015 for the occurrence of endocrine irAE. Thyroid function (TSH, fT4) was routinely assessed at baseline and prior to dosing with pembrolizumab; ACTH, cortisol, FSH and sex hormones were measured on clinical suspicion of hypophysitis or adrenal insufficiency. Baseline population characteristics were: median age 60 years (range 26-94), 65% female and 35% male, unresectable AJCC stage III: 4 pts (5%); - IV: 73 pts (95%) [M1a=3 pts; M1b=6 pts; M1c=64 pts], 35 pts had LDH >ULN (45%). Median follow-up was 19 weeks (range 1-58). A prior history of thyroid disorders was identified in 12 pts. During pembrolizumab therapy a total of 11 pts (14%) experienced a thyroid related irAE (including 2 pts with a prior history of thyroid disorder). Hyperthyroidism occurred in 8 pts (10%; 2 pts grade 1, 5 pts grade 2, 1 pt grade 3). Maximum fT4 levels ranged from 21.6 to > 100 pmol/L (normal range 11.6-22.0 pmol/L). Severe hyperthyroidism requiring therapy with propranolol occurred in 1 pt. Hyperthyroidism was transient in all pts and in 7 cases evolved into hypothyroidism. Hypothyroidism occurred in 11 pts (4 pts grade 1, 7 pts grade 2) and in 4 cases was not preceded by hyperthyroidism. Hypothyroidism required treatment with thyroid hormone substitution in 5 out of 11 pts. Informative test results on the presence of thyroid autoantibodies (anti-TPO and TSI) are available in 6 out of the 12 pts with thyroid irAE. TSI was detected in 1 pt at the time of hyperthyroidism; anti-TPO was detected in 2 pts (in 1 pt at the time of hypo- and in 1 pt at the time of hyperthyroidism). Pembrolizumab treatment was continued during the period of thyroid irAE in 9 cases and was interrupted because of the thyroid irAE in 1 case. In conclusion, thyroid dysfunction is a common irAE in melanoma pts treated with pembrolizumab. Serial measurement of TSH and fT4 is indicated during pembrolizumab treatment. Baseline assessment of thyroid autoantibodies deserves further evaluation as a possible predictive marker for thyroid dysfunction during pembrolizumab treatment. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS corticotropin endogenous compound hydrocortisone propranolol sex hormone thyroid antibody thyroid hormone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) compassionate use melanoma side effect EMTREE MEDICAL INDEX TERMS adrenal insufficiency adult adverse drug reaction aged clinical trial controlled study drug therapy electronic medical record endocrine system female follow up human hyperthyroidism hypophysitis hypothyroidism major clinical study male substitution reaction thyroid function CAS REGISTRY NUMBERS corticotropin (11136-52-0, 9002-60-2, 9061-27-2) hydrocortisone (50-23-7) pembrolizumab (1374853-91-4) propranolol (13013-17-7, 318-98-9, 3506-09-0, 4199-09-1, 525-66-6) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613520128 DOI 10.1210/endo-meetings.2016.THPTA.2.SUN-244 FULL TEXT LINK http://dx.doi.org/10.1210/endo-meetings.2016.THPTA.2.SUN-244 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 87 TITLE Phase II study of pembrolizumab in patients with metastatic castration-resistant prostate cancer previously treated with targeted endocrine therapy and taxane chemotherapy: KEYNOTE-199 AUTHOR NAMES Antonarakis E.S. Drake C.G. Wu H. Poehlein C. De Bono J. AUTHOR ADDRESSES (Antonarakis E.S., eantona1@jhmi.edu) Johns Hopkins University, Sidney Kimmel Cancer Center, Baltimore, United States. (Drake C.G.) Johns Hopkins University Cancer Center, Baltimore, United States. (Wu H.; Poehlein C.) Merck and Co., Inc., Kenilworth, United States. (De Bono J.) Royal Marsden Hospital, London, United Kingdom. CORRESPONDENCE ADDRESS E.S. Antonarakis, Johns Hopkins University, Sidney Kimmel Cancer Center, Baltimore, United States. Email: eantona1@jhmi.edu SOURCE Journal for ImmunoTherapy of Cancer (2016) 4 Supplement 1. Date of Publication: 2016 CONFERENCE NAME 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer, SITC 2016 CONFERENCE LOCATION National Harbor, MD, United States CONFERENCE DATE 2016-11-09 to 2016-11-13 ISSN 2051-1426 BOOK PUBLISHER BioMed Central Ltd. ABSTRACT Background Treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) has focused on suppression of testosterone and androgen receptor signaling, palliative radiation therapy, and chemotherapy. As expression of the programmed death-1 (PD-1) receptor and its ligand PD-L1 is present in mCRPC lesions, particularly after initial treatment with antiandrogen and/or chemotherapy, targeting this pathway may be an attractive treatment option. Pembrolizumab, an anti-PD-1 antibody that blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2, produced durable responses in patients with heavily pretreated PD-L1-positive prostate cancer in the KEYNOTE-028 study. KEYNOTE-199 is a nonrandomized, multinational, open-label phase II study to evaluate pembrolizumab monotherapy in patients with mCRPC previously treated with chemotherapy. Methods Eligible patients must be ≥18 years old with histologically or cytologically confirmed adenocarcinoma of the prostate without small-cell histology, measurable disease per RECIST v1.1 or detectable bone metastases by whole-body bone scintigraphy and no RECIST v1.1 measurable tumors, supplied tumor sample for PD-L1 expression (new or archived), progression of disease within 6 months before screening, and ECOG performance status 0-2. Patients must have been treated with ≥1 targeted endocrine therapy (abiraterone or enzalutamide) and ≤2 chemotherapy regimens, 1 of which must have contained docetaxel. Patients also must have ongoing androgen deprivation with serum testosterone <50 ng/dL. Patients will be enrolled into 1 of 3 cohorts based on PD-L1 status and RECIST v1.1 measurability: patients with PD-L1-positive, RECIST v1.1 measurable disease (cohort 1, n=100), patients with PD-L1-negative, RECIST v1.1 measurable disease (cohort 2, n=100), and patients with bone metastases and RECIST v1.1 nonmeasurable disease (cohort 3, n=50). Patients will receive pembrolizumab 200 mg every 3 weeks until documented confirmed disease progression, unacceptable adverse events (AEs), or illness that prevents further treatment. Imaging response will be assessed every 9 weeks for approximately 1 year and every 12 weeks thereafter, per central imaging vendor review using RECIST v1.1 criteria and the Prostate Cancer Clinical Trials Working Group 3 guidelines. AEs will be monitored throughout the study and graded per Common Terminology Criteria for Adverse Events, version 4.0. Primary end points are the objective response rate and duration of response for cohorts 1 and 2 combined and by each cohort. Key secondary end points include safety and tolerability, disease control rate, radiographic progression-free survival, and overall survival for each cohort and all 3 combined. Exploratory translational analyses and expression of other immune checkpoints will also be evaluated. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS abiraterone androgen docetaxel endogenous compound enzalutamide programmed death 1 ligand 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) castration resistant prostate cancer chemotherapy hormonal therapy male EMTREE MEDICAL INDEX TERMS adult adverse drug reaction bone metastasis bone scintiscanning cancer epidemiology clinical trial consensus development controlled clinical trial controlled study disease control drug therapy exploratory research gene expression histology human human tissue imaging major clinical study monotherapy nomenclature overall survival phase 2 clinical trial progression free survival prostate adenocarcinoma response evaluation criteria in solid tumors safety screening side effect testosterone blood level young adult CAS REGISTRY NUMBERS abiraterone (154229-19-3) docetaxel (114977-28-5) enzalutamide (915087-33-1) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613519020 DOI 10.1186/s40425-016-0172-7 FULL TEXT LINK http://dx.doi.org/10.1186/s40425-016-0172-7 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 88 TITLE Where is the storm coming from: A case of thyroid storm secondary to ipilimumab AUTHOR NAMES Ferdousy F. Williams C.C. Sherman B. Fouty B. Vu M. AUTHOR ADDRESSES (Ferdousy F.; Williams C.C.; Sherman B.; Fouty B.; Vu M.) University of South Alabama, College of Medicine, Mobile, United States. CORRESPONDENCE ADDRESS C.C. Williams, University of South Alabama, College of Medicine, Mobile, United States. SOURCE Chest (2016) 150:4 Supplement 1 (379A). Date of Publication: 1 Oct 2016 CONFERENCE NAME CHEST 2016 CONFERENCE LOCATION Los Angeles, CA, United States CONFERENCE DATE 2016-10-22 to 2016-10-26 ISSN 1931-3543 BOOK PUBLISHER Elsevier B.V. ABSTRACT INTRODUCTION: Checkpoint inhibitor immunotherapy is related to rare immune related adverse events. We present a very rare case of thyroid storm after treatment with ipilimumab in our ICU. To our knowledge this is the second case of thyroid storm reported due to ipilimumab. CASE PRESENTATION: A 49-year-old white male with Stage 3C metastatic melanoma presented with altered mental status, fever, palpitations, and diarrhea. Patient was treated with ipilimuab for the melanoma with the most recent dose received 3 weeks ago. He was treated for meningitis with broad spectrum antibiotics, but did not show much clinical improvement, and required mechanical ventilation for worsening mental status and inability to protect his airway. A thorough investigation for infectious and autoimmune causes was negative. He was persistently tachycardic in the 160s and also developed new onset systolic heart failure. Thyroid function studies showed TSH <0.01 micro IU/ml (normal 0.3-4.7), T3 of 22 pg/ml (normal 2.4-4.2), and free T4 level of 5 ng/dl (normal 0.7-1.6). Based on the Burch and Wartofsky scoring system, the patient was diagnosed with thyroid storm most likely due to ipilimumab. He was treated with hydrocortisone equivalent to prednisone 1 mg/kg, propylthiouricil, Lugol's solution, and betablockers, and responded well to the treatment. He was extubated with gradual improvement of his mental status. DISCUSSION: Ipilimumab is a recombinant human monoclonal antibody to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Blocking CTLA-4 enhances antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for adverse events. Ipilimumab has been associated with a wide spectrum of thyroid function abnormalities, most commonly thyroiditis and/or hypothyroidism in 1-2% of patients. Having a clinical suspicion for thyroid storm can be very challenging since the findings are non-specific and often misdiagnosed as sepsis. While the Burch and Wartofsky scoring system can be used to diagnose thyroid storm, no standardized, universally accepted clinical tools for diagnosis exist. Treatment includes steroids, antithyroid drugs and betablockers. It is recommended to check thyroid function tests before initiating ipilimumab and every three months or sooner if the patient develops symptoms. CONCLUSIONS: It is important to have a very high clincal suspicion for unusual side effects secondary to checkpoint inhibitor therapy. While ipilimuab usually causes other forms of endocrinopathies, clinicians should inlcude thyroid storm in their differential diagnosis in the appropriate clincal setting. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS antibiotic agent beta adrenergic receptor blocking agent cytotoxic T lymphocyte antigen 4 endogenous compound human monoclonal antibody hydrocortisone liothyronine lugol prednisone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) thyroid crisis EMTREE MEDICAL INDEX TERMS adult adverse drug reaction airway artificial ventilation case report congenital malformation controlled study cytotoxic T lymphocyte diagnosis diarrhea differential diagnosis drug therapy fever free thyroxine index gene inactivation heart palpitation human hypothyroidism instrument validation lymphocyte proliferation male meningitis mental health metastatic melanoma middle aged scoring system sepsis side effect symptom systolic heart failure T lymphocyte activation tachycardia thyroid function test thyroiditis tumor immunity CAS REGISTRY NUMBERS hydrocortisone (50-23-7) ipilimumab (477202-00-9) liothyronine (6138-47-2, 6893-02-3) lugol (12298-68-9) prednisone (53-03-2) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613468171 DOI 10.1016/j.chest.2016.08.392 FULL TEXT LINK http://dx.doi.org/10.1016/j.chest.2016.08.392 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 89 TITLE Nivolumab-induced autoimmune diabetic ketoacidosis AUTHOR NAMES Zaied A. Lee A. AUTHOR ADDRESSES (Zaied A.; Lee A.) Mayo Clinic, Jacksonville, United States. CORRESPONDENCE ADDRESS A. Zaied, Mayo Clinic, Jacksonville, United States. SOURCE Chest (2016) 150:4 Supplement 1 (255A). Date of Publication: 1 Oct 2016 CONFERENCE NAME CHEST 2016 CONFERENCE LOCATION Los Angeles, CA, United States CONFERENCE DATE 2016-10-22 to 2016-10-26 ISSN 1931-3543 BOOK PUBLISHER Elsevier B.V. ABSTRACT INTRODUCTION: Nivolumab, a monoclonal antibody against programmed cell death-1 receptor (PD-1), is increasingly used in advanced cancers. PD-1 is responsible for self-tolerance and prevention of autoimmunity. While PD-1 blockage enhances cancer therapy, it's associated with immune-related adverse events (AE). We describe an elderly patient who presented in ketoacidosis due to new-onset diabetes mellitus (DM) after receiving nivolumab CASE PRESENTATION: A 70-year-old man with metastatic renal cell carcinoma presented with dyspnea and abdominal pain. 10 days prior, he received his 3rd cycle of nivolumab. He was tachypneic and hyperpneic with normal auscultation of the lungs. Lab analyses showed hyponatremia, hyperkalemia, and hyperglycemia (878 mg/dL). Prior glucose levels were normal. Arterial blood gas was consistent with metabolic acidosis (see table). Lactic acid level was normal. “Large” serum acetone and urine ketones were detected. Glutamic Acid Decarboxylase (GAD65) antibody was negative. He was diagnosed with diabetic ketoacidosis (DKA) and was treated with fluids, insulin, and electrolytes resulting in resolution of all metabolic derangements. No other precipitating factors were identified. He was diagnosed with insulin-dependent autoimmune DM secondary to nivolumab. Nivolumab was stopped. He was started on pazopanib (tyrosine kinase inhibitor). On 5 months follow up, he continued to require insulin for his DM despite complete discontinuation of nivolumab DISCUSSION: Cancer immunotherapy has opened up novel biologic pathways to target, and is being utilized more in multiple cancers. Because of PD-1's role in immunity, disruption of its pathway has raised concerns for developing autoimmune disorders. While, nivolumab AEs are common and tolerated, clinicians need to be aware of serious AEs like autoimmune endocrinopathies. Trials reported hyperglycemia not uncommonly (0.5-5%). One series estimated the incidence of DM to be 2 per 100,000 personyears. As its use expands, the true risk will become clearer. Despite being a rare toxicity, the health and socioeconomic impact of inducing DM is significant, particularly when presenting with life-threatening DKA CONCLUSIONS: Discussing common AEs and potential serious toxicities of nivolumab should be the base of informed consent process. Importantly, clinicians need to be alerted to the possibility of DKA in patients receiving anti-PD-1 therapy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS acetone electrolyte endogenous compound glucose glutamate decarboxylase 65 antibody glutamate decarboxylase 67 insulin lactic acid pazopanib programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) diabetic ketoacidosis EMTREE MEDICAL INDEX TERMS abdominal pain adverse drug reaction aged arterial gas auscultation autoimmune disease cancer immunotherapy case report clinical trial controlled study diagnosis drug withdrawal dyspnea follow up gene disruption human human tissue hyperglycemia hyperkalemia hyponatremia immunity informed consent ketonuria kidney metastasis liquid male metabolic acidosis side effect toxicity CAS REGISTRY NUMBERS acetone (67-64-1) glucose (50-99-7, 84778-64-3) insulin (9004-10-8) lactic acid (113-21-3, 50-21-5) nivolumab (946414-94-4) pazopanib (444731-52-6, 635702-64-6) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613469122 DOI 10.1016/j.chest.2016.08.26 FULL TEXT LINK http://dx.doi.org/10.1016/j.chest.2016.08.26 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 90 TITLE Analysis of immune checkpoint control protein co-expression in breast and ovarian cancer using novel rabbit monoclonal antibodies and multiplex IHC AUTHOR NAMES Silver M.R. Ziello J.E. Haack H. AUTHOR ADDRESSES (Silver M.R.; Ziello J.E.; Haack H.) CORRESPONDENCE ADDRESS M.R. Silver, SOURCE Cancer Immunology Research (2016) 4:1 Supplement. Date of Publication: 1 Jan 2016 CONFERENCE NAME CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival CONFERENCE LOCATION New York, NY, United States CONFERENCE DATE 2015-09-16 to 2015-09-19 ISSN 2326-6074 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT With an increasing number of biomarkers, and often limited availability of biopsy material, there is a growing need for multiplexed assays for both research and clinical purposes. IHC based solutions are particularly attractive in the field of immuno-oncology, as maintaining special context within the tumor microenvironment provides meaningful, and potentially actionable, information. Immuno-assays with high specificity and sensitivity are a powerful tool; however, there are challenges associated with antibody based multiplexing when more than 2-3 markers are required. A multiplex IHC solution that bypasses antibody species/isotype concerns, while providing signal amplification, was used to examine the coexpression of immune checkpoint control proteins, such as PD-L1, B7-H3, B7-H4, VISTA, in breast and ovarian cancer. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody EMTREE DRUG INDEX TERMS endogenous compound programmed death 1 ligand 1 V set domain containing T cell activation inhibitor 1 EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) breast cancer female gene expression regulation immunohistochemistry Leporidae nonhuman ovary cancer EMTREE MEDICAL INDEX TERMS gene amplification human human tissue species LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613321441 DOI 10.1158/2326-6074.CRICIMTEATIAACR15-A006 FULL TEXT LINK http://dx.doi.org/10.1158/2326-6074.CRICIMTEATIAACR15-A006 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 91 TITLE Phase 3 trial of avelumab (anti-PD-L1) in combination with and/or following platinum-based chemotherapy in patients with untreated ovarian cancer AUTHOR NAMES Ledermann J. Fujiwara K. Vergote I. Oza A. Birrer M. Disilvestro P. Beck J.T. Randall L. Matulonis U. Shnaidman M. Potier H. Mather C.B. Morozov A. Monk B. AUTHOR ADDRESSES (Ledermann J.) UCL Cancer Institute, CR-UK and UCL Cancer Trials Centre, London, United Kingdom. (Fujiwara K.) Saitama Medical University, International Medical Center, Department of Gynecologic Oncology, Yamane-Hidaka-city-Saitama, Japan. (Vergote I.) KU Leuven, Department of Gynecologic Oncology, Leuven, Belgium. (Oza A.) Princess Margaret Cancer Centre, Cancer Clinical Research Unit CCRU, Toronto, Canada. (Birrer M.) Massachusetts General Hospital, Richard B. Simches Research Center, Center for Systems Biology, Boston, United States. (Disilvestro P.) Women and Infants Hospital, Department of Gynecologic Oncology, Providence, United States. (Beck J.T.) Highlands Oncology Group, Department of Medical Oncology, Fayetteville, United States. (Randall L.) UC Irvine Health- Ovarian Cancer Center, Deprartment of Gynecologic Cancer, Orange, United States. (Matulonis U.) Dana-Farber Cancer Institute, Department of Gynecologic Oncology, Boston, United States. (Shnaidman M.) Pfizer Inc., Biostatistics, New York, United States. (Potier H.; Morozov A.) Pfizer Inc., Immuno-Oncology, New York, United States. (Mather C.B.) Pfizer Inc., Immuno-Oncology, Groton, United States. (Monk B.) St. Joseph's Hospital and Medical Center, Center for Women's Health at Dignity Health, Phoenix, United States. CORRESPONDENCE ADDRESS J. Ledermann, UCL Cancer Institute, CR-UK and UCL Cancer Trials Centre, London, United Kingdom. SOURCE International Journal of Gynecological Cancer (2016) 26 Supplement 3 (753). Date of Publication: 1 Oct 2016 CONFERENCE NAME 16th Biennial Meeting of the International Gynecologic Cancer Society CONFERENCE LOCATION Lisbon, Portugal CONFERENCE DATE 2016-10-28 to 2016-10-31 ISSN 1525-1438 BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Background and Aims: PD-L1 is a key therapeutic target in the reactivation of the immune response against cancer. Avelumab∗ (MSB0010718C) is a fully human anti-PD-L1 antibody that has shown promising efficacy and manageable safety in patients with advanced pre-treated ovarian cancer (OC). Chemotherapy has been shown to have immunostimulatory properties. JAVELIN Ovarian 100 (NCT02718417) is an open-label, multicenter, 3-arm trial evaluating avelumab in combination with and/or following first-line (1L) chemotherapy in patients with ovarian cancer. Methods: This trial investigates if avelumab administered in combination with and/or following 1L chemotherapy is superior to chemotherapy alone followed by observation. Eligibility criteria include: newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following debulking surgery or prior to neoadjuvant chemotherapy, irrespective of PD-L1 status. Approximately 951 eligible patients will be randomized (1:1:1) to receive: (A) chemotherapy followed by observation; (B) chemotherapy followed by avelumab; or (C) chemotherapy + avelumab followed by avelumab. Chemotherapy backbone is carboplatin Q3W plus investigator's choice of weekly paclitaxel (80 mg/m(2)) or Q3W paclitaxel (175 mg/m(2)). Avelumab is administered at 10mg/kg Q3W with 1L chemotherapy. Patients in arms B or C who have not progressed after chemotherapy receive maintenance avelumab 10mg/kg Q2W for maximum of 24 months. Neoadjuvant patients in each arm will undergo interval debulking after 3 cycles. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, PFS by Gynecological Cancer InterGroup criteria, maintenance PFS; pCR, PFS2, pharmacokinetics, immunogenicity, quality of life, safety, and biomarkers in tumor and blood. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab platinum programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS endogenous compound paclitaxel EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) chemotherapy ovary cancer EMTREE MEDICAL INDEX TERMS blood cancer epidemiology clinical trial controlled clinical trial controlled study cytoreductive surgery diagnosis drug combination drug therapy Fallopian tube female human immunogenicity major clinical study multicenter study neoadjuvant therapy overall survival peritoneum cancer pharmacokinetics phase 3 clinical trial progression free survival quality of life randomized controlled trial safety CAS REGISTRY NUMBERS avelumab (1537032-82-8) paclitaxel (33069-62-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613200303 DOI 10.1097/01.IGC.0000503327.50238.5c FULL TEXT LINK http://dx.doi.org/10.1097/01.IGC.0000503327.50238.5c COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 92 TITLE Phase 2 trial of dose dense (weekly) paclitaxel with pembrolizumab in platinum resistant recurrent ovarian cancer AUTHOR NAMES Wenham R. Dorman D. Lee J. Apte S. Chon H. Shahzad M. AUTHOR ADDRESSES (Wenham R.; Dorman D.; Apte S.; Chon H.; Shahzad M.) H. Lee Moffitt Cancer Center, Gynecologic Oncology, Tampa, United States. (Lee J.) H. Lee Moffitt Cancer Center, Biostatistics, Tampa, United States. CORRESPONDENCE ADDRESS R. Wenham, H. Lee Moffitt Cancer Center, Gynecologic Oncology, Tampa, United States. SOURCE International Journal of Gynecological Cancer (2016) 26 Supplement 3 (877). Date of Publication: 1 Oct 2016 CONFERENCE NAME 16th Biennial Meeting of the International Gynecologic Cancer Society CONFERENCE LOCATION Lisbon, Portugal CONFERENCE DATE 2016-10-28 to 2016-10-31 ISSN 1525-1438 BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Background and Aims: Recurrent epithelial ovarian, fallopian, and peritoneal cancer (EOC) is an immunogenic tumor and infiltrating lymphocytes express the negative regulatory immune receptor programmed cell death 1 (PD1). Paclitaxel induces proinflammatory cytokine secretion and immune cell activation. Weekly (QW) administration of paclitaxel (P) can have responses in platinum- and taxane-resistant cancers. Methods: Phase 2 study with endpoint of 6-month progression free survival (PFS) of QWP (80 mg/m(2)) with Q3W pembrolizumab (PBro) (200 mg). Secondary endpoints include safety, response rate, disease control rate, duration of response, and median overall survival. Patients (pts) with persistent/recurrent EOC, < 6 months of prior platinum, ≤ 3 prior therapies, measurable or evaluable disease (with CA-125 criteria), standard laboratories, and performance status of 0-2. Two dose level reductions allowed. Tissue evaluation of PD-L1 and immune infiltrates. Genomic blood, peripheral blood mononuclear cells (PBMC) pretherapy, Cycle 2 day 1, and Cycle 4 day 1 are correlative studies. Results: 12 pts enrolled, 7 on treatment. Avg age 64.5 (46-75). Avg time on treatment=4.3 mo. (range 2.7-6.9). Grade (G)3/4 toxicities: 3 G3 toxicities (1 GI, 2 Renal), no G4. Most common AE's (% Patients); anemia (41), low neutrophil count (33), parathesia (25), anxiety, insomnia, pleural effusion, alkaline phosphatasemia, diarrhea, fatigue, rhinitis (16 each). Conclusions: There are no unexpected toxicities and this trial appears to confirm the ability to give weekly P without steroids when combined with PBro. Study is ongoing. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) paclitaxel pembrolizumab platinum EMTREE DRUG INDEX TERMS CA 125 antigen endogenous compound programmed death 1 ligand 1 steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) controlled study dose densification female ovary cancer EMTREE MEDICAL INDEX TERMS adult adverse drug reaction anemia anxiety clinical article clinical trial controlled clinical trial diarrhea disease control drug resistance fatigue human insomnia middle aged neutrophil count overall survival peripheral blood mononuclear cell phase 2 clinical trial pleura effusion progression free survival rhinitis safety side effect toxicity CAS REGISTRY NUMBERS paclitaxel (33069-62-4) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L613200545 DOI 10.1097/01.IGC.0000503327.50238.5c FULL TEXT LINK http://dx.doi.org/10.1097/01.IGC.0000503327.50238.5c COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 93 TITLE Inhibiting cell cycle checkpoints improves the efficacy of chemotherapy in pineoblastoma AUTHOR NAMES Endersby R. Kuchibhotla M. Schoep T. George C. Hii H. Strowger B. Gande S. Kees U. Gottardo N. AUTHOR ADDRESSES (Endersby R.; Kuchibhotla M.; Schoep T.; George C.; Hii H.; Strowger B.; Gande S.; Kees U.; Gottardo N.) Telethon Kids Institute and University of Western Australia, Perth, Australia. (Gottardo N.) Princess Margaret Hospital, Subiaco, Australia. CORRESPONDENCE ADDRESS R. Endersby, Telethon Kids Institute and University of Western Australia, Perth, Australia. SOURCE Neuro-Oncology (2016) 18 Supplement 3 (iii12). Date of Publication: 1 Jun 2016 CONFERENCE NAME 17th International Symposium on Pediatric Neuro-Oncology, ISPNO 2016 CONFERENCE LOCATION Liverpool, United Kingdom CONFERENCE DATE 2016-06-12 to 2016-06-15 ISSN 1523-5866 BOOK PUBLISHER Oxford University Press ABSTRACT Pineoblastoma is an invasive embryonal brain tumour arising in the pineal gland. Although pineoblastoma and other CNS PNETs are biologically distinct from medulloblastoma, due to histologic similarities older children with pineoblastoma have been treated with medulloblastoma regimens: upfront surgery followed by cranio-spinal irradiation and platinum-/alkylatorbased chemotherapy. Infants with pineoblastoma have been treated utilising intensive chemotherapy only strategies to avoid the damaging effects of radiotherapy on developing brain. Whilst outcome for older children is comparable to medulloblastoma, it is dismal in infants. A lack of preclinical models has hindered development of more effective therapies for pineoblastoma. We previously isolated three cell lines from tumour tissue obtained at two separate surgeries from an 8-month-old girl with extensive pineoblastoma. With the aim of repurposing therapeutics, we performed a high-throughput screen of 3915 compounds, including FDA-approved and oncology drugs. This identified 38 effective compounds with diverse mechanisms of action compared to the current drugs used in the clinic. We have further characterised the interactions of several of these compounds with the conventional chemotherapeutics used for treatment. This revealed that several inhibitors targeting cell cycle regulatory kinases enhanced the efficacy of cyclophosphamide. These drug combinations are currently being examined for efficacy in vivo using orthotopic xenograft mouse models. Thus, high-throughput drug screening and in vitro assessment of novel drugs in patient-derived braintumourcells can identify potential new therapies. Assessment of new drug combinations in mouse models will enable the exclusion of potentially ineffective treatments and prioritisation of truly beneficial new treatments for clinical trial. EMTREE DRUG INDEX TERMS cyclophosphamide new drug phosphotransferase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cell cycle checkpoint chemotherapy pineal body tumor EMTREE MEDICAL INDEX TERMS animal experiment animal model animal tissue cell line combination drug therapy drug combination drug therapy female girl high throughput screening hospital in vitro study infant medulloblastoma mouse mouse model nonhuman oncology preclinical study surgery tumor model xenograft CAS REGISTRY NUMBERS cyclophosphamide (50-18-0) phosphotransferase (9031-09-8, 9031-44-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611933927 DOI 10.1093/neuonc/now067.26 FULL TEXT LINK http://dx.doi.org/10.1093/neuonc/now067.26 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 94 TITLE Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced adrenocortical carcinoma from the JAVELIN solid tumor phase Ib trial: Safety and clinical activity AUTHOR NAMES Le Tourneau C. Hoimes C.J. Zarwan C. Wong D.J.L. Bauer S. Wermke M. Claus R. Chin K.M. V on Heydebreck A. Cuillerot J.-M. Gulley J.L. AUTHOR ADDRESSES (Le Tourneau C.; Hoimes C.J.; Zarwan C.; Wong D.J.L.; Bauer S.; Wermke M.; Claus R.; Chin K.M.; V on Heydebreck A.; Cuillerot J.-M.; Gulley J.L.) Institut Curie, Paris, France; Case Comprehensive Cancer Center at Seidman Cancer Center, Cleveland, OH; Lahey Clinic, Burlington, MA; Ronald Reagan UCLA Medical Center, Los Angeles, CA; West German Cancer Center, University Hospital, Essen, Germany; Universitatsklinikum Carl Gustav Carus an der TU Dresden, Dresden, Germany; Universitatsklinikum Freiburg, Freiburg, Germany; EMD Serono, Inc, Billerica, MA; Merck KGaA, Darmstadt, Germany; EMD Serono, Billerica, MA; Genitourinary Malignancies Branch, National Cancer Institute at the National Institutes of Health, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD CORRESPONDENCE ADDRESS C. Le Tourneau, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Avelumab∗ is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report safety and clinical activity of single-agent avelumab in patients (pts) with metastatic adrenocortical carcinoma (mACC), a rare malignancy for which there are limited therapeutic options (NCT01772004 ). Methods: Pts with mACC who had progressed after platinum-based therapy and were unselected for PD- L1 expression were treated with avelumab at 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Prior and ongoing treatment with mitotane was permitted. Tumors were assessed every 6 wks (RECIST 1.1). Objective response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of Oct 23, 2015, 37 pts were treated with avelumab (median 8 wks [range 2-48]) and followed for a median of 13 wks (range 0-58). Median age was 50 y (range 23-71), ECOG PS was 0 (37.8%) or 1 (62.2%), and median number of prior treatments for metastatic disease was 1 (range 0-5). Treatment-related (TR) AEs occurred in 23 pts (62.2%); the most common (> 10%) were nausea (6 [16.2%]), fatigue (5 [13.5%]), pyrexia (5 [13.5%]), and infusion-related reaction (5 [13.5%]), all of grade 1/2. Grade ≥3 TRAEs occurred in 5 pts (13.5%; each 1 event): hyperkalemia, increased ALT, GGT, or transaminase, sepsis, spinal cord infection, and pneumonitis. Potential immune-related TRAEs occurred in 4 pts (10.8%): 3 pts with grade 1/2 events and 1 pt with grade 3 pneumonitis that resolved. There were no treatment-related deaths. Among 19 pts with ≥13 wks f/u, unconfirmed ORR was 10.5% (2 partial responses; 95% CI: 1.3, 33.1). Stable disease was observed in 5 pts (26.3%); disease control rate was 36.8% (7/19). Median PFS was 7.6 wks (95% CI: 5.9, 23.9), and PFS rate at 12 wks was 30.3% (95% CI: 12.3, 50.7). Conclusions: Avelumabshowed an acceptable safety profile and clinical activity in pts with mACC, a dataset representing the first study to date of an anti-PD-(L)1 agent in this rare tumor type. Analyses of activity, including response correlated with PD-L1 expression, are ongoing. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS aminotransferase gamma glutamyltransferase mitotane platinum EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal cortex carcinoma pharmacokinetics safety solid malignant neoplasm EMTREE MEDICAL INDEX TERMS adult adverse drug reaction aged clinical article clinical trial controlled study death disease control drug therapy drug withdrawal fatigue fever gene expression human hyperkalemia infusion related reaction metastasis nausea pneumonia progression free survival response evaluation criteria in solid tumors sepsis spinal cord infection toxicity CAS REGISTRY NUMBERS aminotransferase (9031-66-7) avelumab (1537032-82-8) gamma glutamyltransferase (85876-02-4) mitotane (53-19-0) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611752934 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 95 TITLE Pembrolizumab for advanced papillary or follicular thyroid cancer: Preliminary results from the phase 1b KEYNOTE-028 study AUTHOR NAMES Mehnert J.M. Varga A. Brose M. Aggarwal R.R. Lin C.-C. Prawira A. De Braud F. Tamura K. Doi T. Piha-Paul S.A. Gilbert J. Saraf S. Thanigaimani P. Cheng J.D. Keam B. AUTHOR ADDRESSES (Mehnert J.M.; Varga A.; Brose M.; Aggarwal R.R.; Lin C.-C.; Prawira A.; De Braud F.; Tamura K.; Doi T.; Piha-Paul S.A.; Gilbert J.; Saraf S.; Thanigaimani P.; Cheng J.D.; Keam B.) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Gustave Roussy, Villejuif, France; Hospital of the University of Pennsylvania, Philadelphia, PA; University of California, San Francisco, San Francisco, CA; National Taiwan University Hospital, Taipei, Taiwan; Princess Margaret Cancer Centre, Toronto, ON, Canada; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; National Cancer Center Hospital Tokyo, Tokyo, Japan; National Cancer Center Hospital East, Chiba, Japan; The University of Texas MD Anderson Cancer Center, Houston, TX; Vanderbilt University School of Medicine, Nashville, TN; Merck & Co., Inc., Kenilworth, NJ; Seoul National University Hospital, Seoul, Korea, The Republic of CORRESPONDENCE ADDRESS J.M. Mehnert, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Treatment options are limited for patients (pts) with advanced thyroid cancer. PD-L1 expression in thyroid cancer tumors has been shown to correlate with poor prognosis. Pembrolizumab (pembro), an anti-PD-1 antibody, blocks the interaction between PD-1 and PD-L1 and PD-L2. We assessed the safety and efficacy of pembro in PD-L1+ advanced (unresectable and/or metastatic) thyroid cancer. Methods: KEYNOTE- 028 (NCT02054806 ) is a nonrandomized trial of pembro in 20 types of advanced solid tumors. Key eligibility criteria for this cohort included papillary or follicular subtypes of advanced thyroid cancer, failure of standard therapy, ECOG PS 0-1, and PD-L1 expression in > 1% of tumor or stroma cells by IHC. Pembro 10 mg/kg was given every 2 wk for up to 24 mo or until confirmed progression, intolerable toxicity, death, or withdrawal of consent. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by investigator review. Results: Of the 22 pts enrolled, median age was 60.5 y; 40.9% were male; 68.2% vs 31.8% had papillary vs follicular carcinoma; 36.4% had an ECOG PS of 1; 50.0% received ≥ 2 prior therapies for metastatic disease (18 pts were radioactive iodine refractory; 7 pts received prior sorafenib; 1 pt received prior lenvatinib). Median follow-up duration as of Dec 10, 2015, was 73.5 wk (range, 29.4-87.0). 18 (81.8%) pts had treatment-related adverse events (TRAEs); those occurring in > 15% of pts were diarrhea (n = 7) and fatigue (n = 4). 1 TRAE of grade > 3 (grade 3 colitis) occurred; no pts died or discontinued pembro because of a TRAE. 2 pts had a PR for an ORR (confirmed) of 9.1% (95% CI, 1.1-29.2); median duration of response was not yet reached (range, 35.3-44.1 + wk) by the data cutoff. The stable disease rate was 54.5% (n = 12, 95% CI, 32.2-75.6). The 6-mo OS rate was 100%; the 6-mo PFS rate was 58.7%. At the data cutoff, 6 pts remained on treatment. Conclusions: Pembro shows promising antitumor activity in advanced papillary or follicular thyroid cancer which progressed on standard therapies. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS lenvatinib programmed death 1 ligand 1 radioactive iodine sorafenib EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) disease course follicular carcinoma EMTREE MEDICAL INDEX TERMS adult adverse drug reaction antineoplastic activity clinical article clinical trial colitis controlled clinical trial controlled study death diarrhea drug therapy drug withdrawal fatigue female follow up gene expression human human tissue immunohistochemistry male pharmacokinetics phase 1 clinical trial response evaluation criteria in solid tumors safety stroma cell thyroid metastasis toxicity treatment failure tumor resistance CAS REGISTRY NUMBERS lenvatinib (417716-92-8, 857890-39-2) pembrolizumab (1374853-91-4) sorafenib (284461-73-0) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611753750 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 96 TITLE Safety and clinical activity of anti-programmed death-ligand 1 (PD-L1) antibody (ab) avelumab (MSB0010718C) in advanced thymic epithelial tumors (TETs) AUTHOR NAMES Rajan A. Heery C.R. Perry S. Keen C. Mammen A.L. Berman A.W. Pittaluga S. Lepone L.M. Donahue R.N. Grenga I. Schlom J. Hassan R. Gulley J.L. AUTHOR ADDRESSES (Rajan A.; Heery C.R.; Perry S.; Keen C.; Mammen A.L.; Berman A.W.; Pittaluga S.; Lepone L.M.; Donahue R.N.; Grenga I.; Schlom J.; Hassan R.; Gulley J.L.) Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Biology, National Cancer Institute at the National Institutes of Health, Bethesda, MD; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD; Center for Cancer Research, National Cancer Institute, Bethesda, MD CORRESPONDENCE ADDRESS A. Rajan, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 ab under clinical development. We report safety and clinical activity in patients (pts) with relapsed TETs enrolled in a phase I trial (NCT01772004 ). Methods: Eligibility criteria: > 1 prior standard therapy, no prior immune checkpoint inhibitors, no prior autoimmune disease. Treatment: Avelumab 10-20 mg/kg iv q2 wks until progression or toxicity. Responses were assessed q6 wks by RECIST 1.1. Correlative studies: PD-1, PD-L1 IHC in tumor samples and peripheral blood immune subset analysis. Results: 8 pts were treated: 7 with thymoma (T) and 1 with thymic carcinoma (TC). Median age 53 yrs (39-76). 3 pts with T (2 B3, 1 B2/B3) received Avelumab 20 mg/kg; 4 T (1 B1, 3 B2) and 1 TC received 10 mg/kg. Responses: 2 (29%) pts with T had confirmed PR (1 at 20 mg/kg, 1 at 10 mg/kg), 2 (29%) unconfirmed PR, 2 (29%) SD and 1 (14%) PD; the TC pt had SD. 3 of 4 responses occurred after 1 dose. Treatment-related adverse events (AE, all grades) in > 15% pts were potential immune-related AEs (irAEs) in 5 (63%) pts and fatigue in 4 (50%) pts. Grade > 3 AEs were irAE (G3 in 3 (38%) pts; G4 in 2 (25%) pts) and hypokalemia (G4 in 1 (13%) pt). irAEs included 1 or more of: muscle weakness, myalgia, myositis, respiratory muscle insufficiency, hoarseness, paresthesia, dysphagia, dyspnea, diarrhea and elevated creatine kinase. With oral steroids irAEs resolved rapidly and completely in 3 pts and incompletely in 1 pt. irAEs gradually resolved with additional medications (IVIG, cyclosporine A) in 1 pt. All responders experienced irAEs (myositis in 3 pts, all after 1 dose of Avelumab and enteritis in 1 pt). Response was seen before or shortly after start of steroids in 3 pts suggesting response was related to Avelumab. Decreased CTLA4+ regulatory T cells and the ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose. Conclusions: Avelumab is active in T with 4 of 7 pts having objective responses accompanied by development of irAEs that were generally reversible with oral steroids. Understanding the mechanism of irAEs and developing treatment strategies for this spectrum of toxicity is important. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS creatine kinase cyclosporine programmed death 1 receptor steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) carcinoma pharmacokinetics safety thymoma EMTREE MEDICAL INDEX TERMS adult adverse drug reaction aged autoimmune disease breathing muscle clinical article clinical trial diarrhea disease course dysphagia dyspnea enteritis granulocyte hoarseness human human tissue hypokalemia immunohistochemistry monocyte muscle weakness myalgia myositis paresthesia regulatory T lymphocyte response evaluation criteria in solid tumors suppressor cell toxicity CAS REGISTRY NUMBERS avelumab (1537032-82-8) creatine kinase (9001-15-4) cyclosporin A (59865-13-3, 63798-73-2) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611754703 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 97 TITLE Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity AUTHOR NAMES Disis M.L. Patel M.R. Pant S. Hamilton E.P. Lockhart A.C. Kelly K. Beck J.T. Gordon M.S. Weiss G.J. Taylor M.H. Chaves J. Mita A.C. Chin K.M. Von Heydebreck A. Cuillerot J.-M. Gulley J.L. AUTHOR ADDRESSES (Disis M.L.; Patel M.R.; Pant S.; Hamilton E.P.; Lockhart A.C.; Kelly K.; Beck J.T.; Gordon M.S.; Weiss G.J.; Taylor M.H.; Chaves J.; Mita A.C.; Chin K.M.; Von Heydebreck A.; Cuillerot J.-M.; Gulley J.L.) University of Washington, Seattle, WA; Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; University of Oklahoma Health Sciences Center, Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK; Sarah Cannon Research Institute/Tennessee Oncology, LLC, North Nashville, TN; Washington University School of Medicine in St. Louis, St. Louis, MO; UC Davis Comprehensive Cancer Center, Sacramento, CA; Highlands Oncology Group, Fayetteville, AR; Pinnacle Oncology Hematology/HonorHealth Research Institute, Scottsdale, AZ; Cancer Treatment Centers of America, Goodyear, AZ; Knight Cancer Institute, Oregon Health and Science University, Portland, OR; Northwest Medical Specialties, Tacoma, WA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; EMD Serono, Inc, Billerica, MA; Merck KGaA, Darmstadt, Germany; EMD Serono, Billerica, MA; Genitourinary Malignancies Branch, National Cancer Institute at the National Institutes of Health, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD CORRESPONDENCE ADDRESS M.L. Disis, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Avelumab∗ is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report safety and clinical activity of avelumab in patients (pts) with recurrent/refractory ovarian cancer (OC; NCT01772004 ). Methods: Pts with advanced OC unselected for PD-L1 expression received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by immunohistochemistry. Results: As of Oct 23, 2015, 124 pts were treated with avelumab (median 12 wks [range 2-54]) and followed for a median of 54 wks (range 11-101). Median age was 62 y (range 27-84), ECOG PS was 0 (47.6%) or 1 (52.4%), and median number of prior therapies was 4 (range 1-13). Treatment-related (TR) AEs occurred in 82 pts (66.1%); most common ( 10%) were fatigue (13.7%), infusion-related reaction (12.1%), and diarrhea (11.3%), all of grade 1/2. Grade 3/4 TRAEs were reported in 8 pts (6.5%); of these, only increased lipase occurred in > 1 pt (n = 2). There were no treatment-related deaths. ORR was 9.7% (95% CI: 5.1-16.3) based on 12 partial responses; 6 were ongoing. Stable disease was observed in 55 pts (44.4%); disease control rate was 54.0%. PD-L1 expression was evaluable in 74 pts (59.7%). Using a ≥1% cutoff for tumor cell staining, 57/74 (77.0%) were PD-L1+ and ORR was 12.3% in PD-L1+ (7/57; 95% CI: 5.1, 23.7) vs 5.9% in PD-L1- pts (1/17; 95% CI: 0.1, 28.7). Overall, median PFS was 11.3 wks (95% CI: 6.1, 12.0) and median OS was 10.8 mos (95% CI: 7.0, 16.1). Conclusions: Single-agent avelumabshowed an acceptable safety profile and clinical activity in heavily pretreated pts with OC. These data represent the largest study of anti-PD(L)1 agents in pts with OC to date. The potential relationship between biomarkers, such as germline BRCA mutational status, and the probability of response is being investigated. Randomized phase 3 trials of avelumab in OC are underway. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab programmed death 1 ligand 1 EMTREE DRUG INDEX TERMS triacylglycerol lipase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) ovary cancer pharmacokinetics safety solid malignant neoplasm EMTREE MEDICAL INDEX TERMS adult adverse drug reaction aged clinical trial controlled clinical trial controlled study death diarrhea disease control disease duration drug therapy drug withdrawal fatigue gene expression germ line human human tissue immunohistochemistry infusion related reaction major clinical study overall survival probability progression free survival randomized controlled trial response evaluation criteria in solid tumors toxicity tumor cell CAS REGISTRY NUMBERS avelumab (1537032-82-8) triacylglycerol lipase (9001-62-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611753805 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 98 TITLE Avelumab (MSB0010718C; anti-PD-LI) ± pegylated liposomal doxorubicin vs pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer: The phase III JAVELIN Ovarian 200 trial AUTHOR NAMES Pujade-Lourraine E. Colombo N. Disis M.L. Fujiwara K. Ledermann J.A. Mirza M.R. Richardson G.E. Beck J.T. Gaillard S. Haney P. Shnaidman M. Morozov A. Monk B.J. AUTHOR ADDRESSES (Pujade-Lourraine E.; Colombo N.; Disis M.L.; Fujiwara K.; Ledermann J.A.; Mirza M.R.; Richardson G.E.; Beck J.T.; Gaillard S.; Haney P.; Shnaidman M.; Morozov A.; Monk B.J.) Hopital Hotel Dieu, Paris, France; European Institute of Oncology and University of Milan- Bicocca, Milan, Italy; University of Washington, Seattle, WA; Saitama Medical University International Medical Center, Hidaka, Japan; University College London, London, United Kingdom; Department of Oncology 5073 Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; The Szalmuk Family Department of Medical Oncology, Cabrini Health, Malvern, Australia; Highlands Oncology Group, Fayetteville, AR; Duke Cancer Institute, Durham, NC; Pfizer, New York, NY; Pfizer Inc, New York NY; University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, AZ CORRESPONDENCE ADDRESS E. Pujade-Lourraine, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Avelumab∗ is a fully human anti-PD-L1 IgG1 antibody that has shown promising efficacy and an acceptable safety profile in heavily pretreated patients (pts) with recurrent ovarian cancer. This openlabel, multicenter, 3-arm, phase 3 trial (NCT02580058 ) compares avelumab ± pegylated liposomal doxorubicin (PLD) vs PLD alone in pts with platinum-resistant/refractory ovarian cancer, and is the first phase 3 trial of a checkpoint inhibitor in ovarian cancer. Methods: The primary objective of this global, multicenter trial is to demonstrate superiority of avelumab ± PLD vs PLD alone, defined by overall survival (OS). Key eligibility criteria include: histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer; up to 3 prior lines of chemotherapy for platinum-sensitive disease (platinum-containing regimen as most recent); and no prior therapy for platinum-resistant disease. Pts are not preselected for PD-L1 expression. Approximately 550 eligible patients will be randomized to receive either avelumab (10 mg/kg as a 1h intravenous [IV] infusion Q2W) ± PLD (40 mg/m(2) as a 1h IV infusion Q4W) or PLD alone (40 mg/m(2) as a 1h IV infusion Q4W). Treatment is given until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include objective response, progression-free survival, duration of response, disease control, pharmacokinetics, immunogenicity, quality of life (assessed via EORTC QLQ-C30, EORTC QLQ-OV38, FOSI, and EQ-5D-5L), safety as per NCI-CTCAE v4.03, and tumor biomarkers, including PD-L1 expression and tumor infiltrating CD8+ T lymphocytes by IHC and tissue expression of immune regulators. Responses are evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) avelumab doxorubicin platinum EMTREE DRUG INDEX TERMS programmed death 1 ligand 1 tumor marker EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) drug resistance ovary carcinoma EMTREE MEDICAL INDEX TERMS cancer epidemiology CD8+ T lymphocyte chemotherapy clinical trial controlled clinical trial controlled study disease control drug therapy drug withdrawal female gene expression human human tissue immunogenicity immunohistochemistry infusion intravenous drug administration major clinical study multicenter study overall survival peritoneum cancer pharmacokinetics phase 3 clinical trial progression free survival quality of life randomized controlled trial response evaluation criteria in solid tumors safety single blind procedure toxicity uterine tube carcinoma CAS REGISTRY NUMBERS avelumab (1537032-82-8) doxorubicin (23214-92-8, 25316-40-9) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611756038 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 99 TITLE Does immune checkpoint inhibitor-induced thyroid dysfunction impact on side effect profile? A restrospective cohort study AUTHOR NAMES Gleeson J.P. Ellis H. Prior L.M. Watson G.A. Nugent K. Lim M.C.J. Harrold E. O'Leary C.G. Kelly D. Kelly C.M. McCaffrey J. AUTHOR ADDRESSES (Gleeson J.P.; Ellis H.; Prior L.M.; Watson G.A.; Nugent K.; Lim M.C.J.; Harrold E.; O'Leary C.G.; Kelly D.; Kelly C.M.; McCaffrey J.) MMUH, Dublin, Ireland; Mater Misericordiae University Hospital, Dublin, Ireland; Mater Misericordiae, Dublin, Ireland; Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland CORRESPONDENCE ADDRESS J.P. Gleeson, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: The immune checkpoint inhibitors have the reported class effects of inducing hypo- or hyperthyroidism in a small but significant number of patients. However, the reported rates of these vary by study. Anecdotally, we have seen a correlation between thyroid dysfunction and adverse side effect profile. We aimed to determine the rates of immune checkpoint inhibitor-induced thyroid dysfunction in our centre and assess the impact of this on side effect frequency. Methods: All patients who received one or more of the immune checkpoint inhibitors over a 5-year period, between January 1st 2010 and December 31st 2015 were analysed and their charts reviewed retrospectively. Patients on active unpublished clinical trials were excluded due to data rights issues. Measures recorded included patient demographics, treatment type and cycles, TSH & free T(4) , and all side effects recorded during the treatment period, classified by CTC AE v4.0. Thyroid dysfunction was defined as TSH outside the laboratory reference range. Results were analysed using SPSS v22.0. Results: 43 patients received ipilimumab, nivolumab or pembrolizumab. 20 patients met the inclusion criteria and received a total of 27 treatments comprising 155 treatment cycles (Mean: 5.8, Range: 1-15). Thyroid dysfunction was seen in 25% (5/20) of patients. A positive correlation was seen between thyroid dysfunction and increasing number of side effects (R = 0.76), however this was not statistically significant (p = 0.36). Thyroid dysfunction onset immediately preceded discontinuation of treatment due to either progression or serious adverse events in 80% (4/5) of those patients. Conclusions: Immune checkpoint inhibitor use in our institute cause thyroid dysfunction at rates higher than those reported in the literature. Thyroid dysfunction is associated with a higher rate of all grade side effects in these patients. This study supports the hypothesis that immune checkpoint inhibitor-induced thyroid dysfunction impacts the side effect profile of patients on these therapies and may impact disease progression or treatment cessation due to serious adverse events. Further research in this area and a larger study is warranted. EMTREE DRUG INDEX TERMS ipilimumab nivolumab pembrolizumab thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cohort analysis side effect thyroid disease EMTREE MEDICAL INDEX TERMS adverse drug reaction clinical article clinical trial controlled study disease course drug therapy free thyroxine index human CAS REGISTRY NUMBERS ipilimumab (477202-00-9) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) thyrotropin (9002-71-5) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611755282 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 100 TITLE Thyroid-related laboratory abnormalities to predict treatmentlimiting adverse events in melanoma patients treated with immune checkpoint blockade AUTHOR NAMES Altman D. Weight R.M. Shah M.R. Orloff M.M. Sharpe-Mills E. Mastrangelo M.J. Sato T. AUTHOR ADDRESSES (Altman D.; Weight R.M.; Shah M.R.; Orloff M.M.; Sharpe-Mills E.; Mastrangelo M.J.; Sato T.) Thomas Jefferson University, Philadelphia, PA; Thomas Jefferson University Hospital, Philadelphia, PA; Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA CORRESPONDENCE ADDRESS D. Altman, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Checkpoint inhibitors have been shown to improve outcomes in patients with metastatic cutaneous melanoma. Thyroid-related laboratory abnormalities are one of the most common abnormalities seen with these treatments. We hypothesized that thyroidrelated laboratory abnormalities predict future treatment-limiting immune-related adverse events (irAEs). Methods: An exploratory study was conducted in melanoma patients (n = 85) who have received anti-CTLA-4 antibody alone (n = 26), anti-PD-1 antibody alone (n = 26) or both (n = 23) at Thomas Jefferson University. Data were collected at baseline and at the time of individual treatments by a retrospective review of electronic medical records. irAEs were categorized into the following: hypophysitis, thyroid dysfunction, lipase elevation, pneumonitis, colitis, transaminitis, acute kidney injury, and diabetes. Results: Incidence and time-to-onset in days of irAEs is shown in table. Number of patients experiencing 0, 1, ≥ 2 irAEs was 35%, 26% and 39% respectively. It is of note that 85.7% (18/21) patients with thyroid-related laboratory abnormalities subsequently developed a serious irAE that required discontinuation of treatment (pneumonitis n = 1, colitis n = 4, hepatitis n = 7, AKI n = 1, DM n = 1, hypophysitis n = 2, thyroid disease n = 2) and this is much higher in incidence compared to those without thyroid-related laboratory abnormalities (P < 0.05). Conclusions: Incidence of individual irAEs was in line with previously published rates. Thyroid-related laboratory abnormalities had a statistically significant correlation (85.7%) with subsequent development of a treatment-limiting irAE. (Table Presented). EMTREE DRUG INDEX TERMS ipilimumab programmed death 1 receptor triacylglycerol lipase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adverse drug reaction melanoma thyroid disease EMTREE MEDICAL INDEX TERMS acute kidney failure clinical trial colitis controlled study diabetes mellitus electronic medical record exploratory research hepatitis human hypertransaminasemia hypophysitis major clinical study pneumonia retrospective study university CAS REGISTRY NUMBERS ipilimumab (477202-00-9) triacylglycerol lipase (9001-62-1) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611755328 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 101 TITLE A phase II single arm multi-center trial evaluating the efficacy of pembrolizumab in the treatment of patients (pts) with incurable platinum refractory germ cell tumors (GCT) AUTHOR NAMES Adra N. Ammakkanavar N. Radovich M. Vaughn D.J. Albany C. Einhorn L.H. Hanna N.H. AUTHOR ADDRESSES (Adra N.; Ammakkanavar N.; Radovich M.; Vaughn D.J.; Albany C.; Einhorn L.H.; Hanna N.H.) Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Indiana University, Indianapolis, IN; Indiana University School of Medicine, Indianapolis, IN; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA CORRESPONDENCE ADDRESS N. Adra, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Initial cisplatin-based combination chemotherapy will cure 80% of pts with metastatic GCT. Pts who relapse after initial chemotherapy can still be cured with second and even third-line regimens. These regimens include high-dose chemotherapy (HDCT) or salvage standard-dose chemotherapy (SDCT). Despite remarkable results with salvage chemotherapy, about 15% of pts with metastatic GCT are currently incurable and have limited further treatment options. Tumors utilize the programmed death receptor 1 (PD-1) pathway to suppress immune control. Pembrolizumab is a potent highly selective IgG4 humanized monoclonal antibody designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab has demonstrated activity in various malignancies. Investigating immune therapy with pembrolizumab is a novel approach for salvage therapy in pts with metastatic GCT. Methods: This is a multi-center, single arm, open label phase 2 trial of pembrolizumab 200mg IV Q3weeks as salvage therapy for pts with incurable GCT. Eligible pts are adult males or females with metastatic GCT (seminoma or non-seminoma) who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (HDCT or SDCT). Pts with treated stable brain metastasis are eligible. Treatment with systemic corticosteroids/immunosuppressants within 7 days of first trial treatment is not permitted. All pts must provide a biopsy sample for PD-L1 expression evaluation and other exploratory analyses including tumor infiltrating lymphocyte and gene expression analysis. Pts are eligible irrespective of PD-L1 expression status. Pembrolizumab will be given for up to 52 weeks or until disease progression or unacceptable toxicity. Primary objective is overall response rate (ORR) using immune related response criteria (irRC) and secondary objectives are ORR using RECIST criteria, assess toxicity and tolerability of pembrolizumab, and duration of disease response. Using a Simon two-stage minimax design, we plan to enroll a total of 20 pts. This study is currently enrolling pts. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab platinum EMTREE DRUG INDEX TERMS cisplatin corticosteroid death receptor immunoglobulin G4 immunosuppressive agent ligand programmed death 1 ligand 1 programmed death 1 ligand 2 programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) comparative effectiveness drug therapy seminoma EMTREE MEDICAL INDEX TERMS adult biopsy brain metastasis chemotherapy clinical article clinical trial controlled clinical trial controlled study disease duration drug megadose exploratory research extracorporeal membrane oxygenation device female gene expression gene inactivation human human tissue immunotherapy male multicenter study phase 2 clinical trial response evaluation criteria in solid tumors salvage therapy toxicity tumor associated leukocyte CAS REGISTRY NUMBERS cisplatin (15663-27-1, 26035-31-4, 96081-74-2) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611755310 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 102 TITLE Specific gene signatures and oligo clonal expansion of b cell repertoire with responders of anti-PD-1 antibody, nivolumab for ovarian cancer: Novel predictive biomarkers AUTHOR NAMES Hamanishi J. Murakami R. Mandai M. Matsumura N. Abiko K. Yamaguchi K. Baba T. Konishi I. AUTHOR ADDRESSES (Hamanishi J.; Murakami R.; Mandai M.; Matsumura N.; Abiko K.; Yamaguchi K.; Baba T.; Konishi I.) Kyoto University, Kyoto, Japan; Kinki University Faculty of Medicine, OsakaSayama, Japan CORRESPONDENCE ADDRESS J. Hamanishi, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Previously we reported a phase II clinical trial for platinum resistant ovarian cancer (n = 20) with anti PD1 antibody, nivolumab and showed RR was 15% including two CRs and one PR (Hamanishi. JCO. 2015). Here we present biomarker data using the tumor and blood samples from patients in this clinical trial. Methods: RNA expression microarray of tumor samples was applied to gene signature of ovarian cancers including clear cell (CCC) gene signature (Yamaguchi. Oncogene 2008) and four gene signatures (Proliferative, Mesenchymal, Differentiated and Immunoreactive) of The Cancer Genome Atlas (Verhaak. JCI 2013) by scoring with ssGSEA. Additionally, we analyzed TCR (αand βchain) and BCR (IgG and IgM) repertoires in 64 blood samples from 20 patients treated with nivolumab throughout the time courses of treatment with an unbiased repertoire analyses. The diversity of TCR and BCR repertoires were compared with ShannonWeaver index (SWI) between clinical responders and nonresponders. RNA expression microarray with blood samples of both preand posttreatment with Nivolumab was analyzed. Results: ssGSEA revealed the CCC signature score was significantly high in two CRs (p = 0.005), while proliferative signature scores were significantly higher in the patients with a PD. BCR repertoire analyses of post treatment in responders revealed significant decreasing of diversity of BCRIgG repertoires compared to nonresponders transiently (SWI, 0.84 vs 1.04, p < 0.05), while over 100 days later, the diversity of IgGBCR went back to original expansion. However the diversity of TCRs nor BCRIgM repertoire were not affected by nivolumab. RNA microarray with blood samples of post treatment in responders showed several B cell related genes such as IL1R2, CD24,CD37 were upregulated compared to in nonresponders (p < 0.05, each). Conclusions: This study, to our knowledge, is the first to describe upregulation of specific gene signatures of tumors and transient oligo clonal expansion of B cell with nivolumab for ovarian cancer. B cell analysis may lead to the early response biomarker and novel antitumor monitoring of nivolumab treatment. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab programmed death 1 receptor EMTREE DRUG INDEX TERMS biological marker CD24 antigen CD37 antigen immunoglobulin G immunoglobulin M interleukin 1 receptor type II platinum T lymphocyte receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) B lymphocyte genetic marker ovary cancer EMTREE MEDICAL INDEX TERMS alpha chain beta chain cancer epidemiology clinical trial DNA microarray drug resistance drug therapy gene expression human human tissue major clinical study oncogene upregulation CAS REGISTRY NUMBERS immunoglobulin G (97794-27-9) immunoglobulin M (9007-85-6) nivolumab (946414-94-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611752912 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 103 TITLE Phase I/II study of niraparib plus pembrolizumab in patients with triple-negative breast cancer or recurrent ovarian cancer (KEYNOTE-162) AUTHOR NAMES Konstantinopoulos P. Moore K.N. Sachdev J.C. Mita M.M. Vinayak S. Seward S.M. Karantza V. Aktan G. Ferguson A. Bobilev D. Matulonis U.A. AUTHOR ADDRESSES (Konstantinopoulos P.; Moore K.N.; Sachdev J.C.; Mita M.M.; Vinayak S.; Seward S.M.; Karantza V.; Aktan G.; Ferguson A.; Bobilev D.; Matulonis U.A.) Dana-Farber Cancer Institute, Boston, MA; University of Oklahoma Health Sciences Center, Oklahoma City, OK; HonorHealth, Scottsdale, AZ; Cedars Sinai Medical Group, Los Angeles, CA; Case Comprehensive Cancer Center, Cleveland, OH; Karmanos Cancer Center, Detroit, MI; Merck & Co., Inc., Kenilworth, NJ; TESARO, Inc., Waltham, MA; Tesaro, Inc., Waltham, MA CORRESPONDENCE ADDRESS P. Konstantinopoulos, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Homologous recombination defects are common in triple-negative breast cancer and high-grade serous ovarian cancer. Both niraparib, a highly selective inhibitor of PARP1/2, and pembrolizumab, a monoclonal antibody that blocks binding of the immune checkpoint receptor programmed death-1 (PD-1) to its ligands (PD-L1/2) and alleviates negative regulation of immune responses to cancer cells, have demonstrated single-agent antitumor activity in patients with breast or ovarian cancer. Combinations of PARP inhibitors with immune checkpoint inhibitors have shown synergistic effects in preclinical tumor models, suggesting that co-treatment with these drugs may improve clinical efficacy compared with monotherapy. This multicenter, open-label phase 1/2 study is evaluating niraparib plus pembrolizumab in metastatic triple-negative breast cancer and advanced ovarian cancer. Methods: Eligible patients have triple-negative breast cancer and ≤ 3 lines of prior chemotherapy (≤ 2 lines for the phase 2 portion) in the metastatic setting or recurrent, platinum-resistant ovarian cancer and ≤ 4 lines of prior chemotherapy (≤ 3 lines for the phase 2 portion) for advanced disease. Patients must have measurable lesions per RECIST v1.1 and no prior treatment with a PARP inhibitor or an anti-PD-1 or anti-PD-L1/2 agent. The phase 1 portion is enrolling K18 patients to identify the recommended phase 2 dose (RP2D) and schedule of niraparib (starting dose: 200 mg orally once daily) combined with pembrolizumab (200 mg IV on day 1 of 21-day cycles). The phase 2 portion will enroll patients with triple-negative breast cancer or ovarian cancer (ft(48 of each) to receive the RP2D and schedule of niraparib plus pembrolizumab. Tumors will be assessed per RECIST v1.1 and immune-related RECIST (irRECIST), a modified version to assess responses to immunotherapies. The primary endpoint of the phase 2 portion is objective response rate (ORR) per RECIST v1.1. Secondary endpoints are ORR per irRECIST; duration of response, disease control rate, and progression-free survival per RECIST and irRECIST; and overall survival. Niraparib pharmacokinetics and biomarkers will be investigated. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) niraparib pembrolizumab EMTREE DRUG INDEX TERMS platinum programmed death 1 ligand 1 programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) ovary cancer triple negative breast cancer EMTREE MEDICAL INDEX TERMS cancer epidemiology clinical article clinical trial controlled clinical trial controlled study disease control drug resistance drug therapy human immunotherapy overall survival patient history of chemotherapy pharmacokinetics phase 1 clinical trial phase 2 clinical trial progression free survival response evaluation criteria in solid tumors tumor resistance CAS REGISTRY NUMBERS niraparib (1038915-60-4) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611756014 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 104 TITLE Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders (AD) or major toxicity with ipilimumab (IPI) AUTHOR NAMES Menzies A.M. Johnson D.B. Ramanujam S. Atkinson V. Wong A.N.M. Park J.J. McQuade J.L. Shoushtari A.N. Tsai K.K. Eroglu Z. Klein O. Hassel J.C. Sosman J.A. Guminski A. Sullivan R.J. Ribas A. Carlino M.S. Davies M.A. Sandhu S.K. Long G.V. AUTHOR ADDRESSES (Menzies A.M.; Johnson D.B.; Ramanujam S.; Atkinson V.; Wong A.N.M.; Park J.J.; McQuade J.L.; Shoushtari A.N.; Tsai K.K.; Eroglu Z.; Klein O.; Hassel J.C.; Sosman J.A.; Guminski A.; Sullivan R.J.; Ribas A.; Carlino M.S.; Davies M.A.; Sandhu S.K.; Long G.V.) Melanoma Institute Australia, Royal North Shore Hospital, The University of Sydney, North Sydney, Australia; Vanderbilt University, Nashville, TN; Melanoma Institute Australia, North Sydney, Australia; Princess Alexandra Hospital, Woolloongabba, Australia; Peter MacCallum Cancer Centre, East Melbourne, Australia; Crown Princess Mary Cancer Centre, Westmead, Australia; The University of Texas MD Anderson Cancer Center, Houston, TX; Memorial Sloan Kettering Cancer Center, New York, NY; UC San Francisco, San Francisco, CA; Moffitt Cancer Center, Tampa, FL; Medical Oncology Unit, Austin Health, Heidelberg, Australia; University Hospital Heidelberg, Department of Dermatology and National Center for Tumor Diseases, Heidelberg, Germany; Vanderbilt-Ingram Cancer Center, Nashville, TN; Melanoma Institute Australia, Sydney, Australia; Massachusetts General Hospital, Boston, MA; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; Westmead Hospital and Melanoma Institute Australia, Sydney, Australia; Peter MacCallum Cancer Center, Melbourne, Australia; Melanoma Institute Australia and The University of Sydney, North Sydney, Australia CORRESPONDENCE ADDRESS A.M. Menzies, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Anti-PD1-antibodies (PD1) have activity in many cancers, and are standard care for melanoma, lung and renal cancer. All trials excluded patients (pts) with significant preexisting AD or major immune-related adverse events (irAEs) with IPI. We sought to explore the safety and efficacy of PD1 in such pts. Methods: Pts with advanced melanoma and preexisting AD and/or major irAEs with prior IPI (requiring systemic immunosuppression, [IS]) treated with PD1 were retrospectively identified. Data regarding AD, IPI and PD1 treatments, toxicity and outcome were examined. Results: 119 pts were included, 95 with prior IPI. 109 received pembrolizumab, 10 nivolumab. 86 (72%) had 3 months (mo) follow-up, median (med) 4.6 mo, with med PFS 6.8 mo. 31 (26%) had died. Of 52 pts with preexisting AD, 15 (29%) had active symptoms at PD1 start and 16 (31%) were on IS. The ORR was 33%. 20 (38%) flared with PD1 after a med 1.3 mo, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 1/2 with scleroderma, 2/2 with immune thrombocytopaenic purpura, 3/8 with psoriasis, 1/4 with Graves' disease, 0/6 with gastrointestinal (GI) (including 3 Crohn's disease) and 0/5 with neurological disorders. 3 (6%) had grade (G) 3 flare, and 2 (4%) discontinued PD1 for flare. 15 (29%) developed other irAEs (5 G3), 3 (6%) discontinued PD1. 67 pts had irAEs requiring IS with prior IPI (9 G2, 51 G3, 7 G4), including 47 with G3 colitis (15 had infliximab), 2 with G4 hepatitis (1 had antithymocyte globulin), and 9 with hypophysitis. All irAEs except hypophysitis had resolved at PD1 start except in 1 pt (arthritis), 5 were on IS at PD1 start. The ORR was 40%. 2 (3%) had recurrence of IPI irAEs with PD1 (arthritis, colitis), but 23 (34%) developed new irAEs (13, 19% G3), and 11 (16%) discontinued PD1. There were no treatment related deaths. Conclusions: PD1 have efficacy in pts with preexisting AD and/or major irAEs with IPI. PD1 may flare preexisting AD, particularly rheumatologic, but GI and neurological disorders may flare less. In pts with prior major irAEs with IPI recurrence of the same irAE is rare, but new irAEs occur. The rate of irAEs in these pts appears higher than in clinical trial pts. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab programmed death 1 receptor EMTREE DRUG INDEX TERMS infliximab nivolumab pembrolizumab thymocyte antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) Graves disease melanoma toxicity EMTREE MEDICAL INDEX TERMS adverse drug reaction clinical trial Crohn disease death follow up gastrointestinal disease hepatitis human hypophysitis idiopathic thrombocytopenic purpura immunosuppressive treatment major clinical study neurologic disease psoriasis relapse rheumatic polymyalgia rheumatoid arthritis safety scleroderma Sjoegren syndrome CAS REGISTRY NUMBERS infliximab (170277-31-3) ipilimumab (477202-00-9) nivolumab (946414-94-4) pembrolizumab (1374853-91-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611754069 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 105 TITLE Phase II trial of dose dense (weekly) paclitaxel with pembrolizumab (MK-3475) in platinum-resistant recurrent ovarian cancer AUTHOR NAMES Wenham R.M. Apte S.M. Shahzad M.M. Lee J.K. Dorman D. Chon H.S. AUTHOR ADDRESSES (Wenham R.M.; Apte S.M.; Shahzad M.M.; Lee J.K.; Dorman D.; Chon H.S.) Moffitt Cancer Center, Tampa, FL; Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; H.Lee Moffitt Cancer Center and Research Institute, Tampa, FL; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL CORRESPONDENCE ADDRESS R.M. Wenham, SOURCE Journal of Clinical Oncology (2016) 34 Supplement 15. Date of Publication: 1 May 2016 CONFERENCE NAME 2016 Annual Meeting of the American Society of Clinical Oncology, ASCO 2016 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2016-06-03 to 2016-06-07 ISSN 1527-7755 BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Recurrent epithelial ovarian, fallopian, and peritoneal cancer (EOC) is the leading cause of gynecologic cancer death. EOC is an immunogenic tumor and infiltrating lymphocytes express the negative regulatory immune receptor programmed cell death 1 (PD1). Paclitaxel induces proinflammatory cytokine secretion and immune cell activation. Weekly (QW) administration of paclitaxel (P) can have responses in platinum- and taxaneresistant cancers and is considered one of the preferred regimens to treat these cancers. Methods: This is a phase 2 study with a primary endpoint to estimate the 6-month progression free survival (PFS) of QWP with Q3W pembrolizumab (PBro) and to compare with historical QWP. Secondary endpoints include safety, response rate, disease control rate, duration of response, and median overall survival. Subjects must have persistent or recurrent EOC within 6 months of prior platinum therapy and may have had up to 3 prior therapies (but no QWP or prior immunotherapy). They may have measurable or nonmeasurable disease (provided CA-125 criteria are met). Standard laboratory parameters must be met and they must have a performance status of 0-2. P is given as 80 mg/m(2) QW with PBro at 200 mg Q3W. Two dose level reductions are allowed. First cycle is 4 weeks with an initial test dose week of P for evaluation of allergic reactions. Subsequent infusions are given without steroids. Archival tissue or core biopsy is required for evaluation of PD-L1 and immune infiltrates. Genomic blood is collected pretherapy and peripheral blood mononuclear cells (PBMC) are collected pretherapy, Cycle 2 day 1, and Cycle 4 day 1 for additional correlative studies. This trial will have 37 evaluable patients enrolled. Under the assumption that the 6-month PFS in the historical control arm is 0.25, it is expected that treatment arm will result in a 50% reduction in the risk of progression at 6 months (6-mo PFS = 0.5). Currently, 10 patients have been enrolled. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) paclitaxel pembrolizumab platinum EMTREE DRUG INDEX TERMS CA 125 antigen programmed death 1 ligand 1 steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) dose densification drug resistance ovary cancer EMTREE MEDICAL INDEX TERMS allergic reaction biopsy clinical article clinical trial controlled clinical trial disease control drug therapy human human tissue immunotherapy infusion overall survival peripheral blood mononuclear cell phase 2 clinical trial progression free survival safety CAS REGISTRY NUMBERS paclitaxel (33069-62-4) pembrolizumab (1374853-91-4) platinum (7440-06-4) LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L611756233 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 106 TITLE Hypophysitis associated with ipilimumab, a novel immunotherapy for metastatic melanoma: Analysis of 26 cases AUTHOR NAMES Min L. Hodi F.S. Carroll R.S. Kaiser U.B. AUTHOR ADDRESSES (Min L.) Brigham and Women's Hospital, Harvard Medical School, Boston, United States. (Hodi F.S.) Dana-Farber Cancer Institute, Boston, United States. (Carroll R.S.; Kaiser U.B.) Brigham and Women's Hospital, Harvard Medical School, Division of Endocrinology/Diabetes, Boston, United States. CORRESPONDENCE ADDRESS L. Min, Brigham and Women's Hospital, Harvard Medical School, Boston, United States. SOURCE Endocrine Reviews (2014) 35 SUPPL. 3. Date of Publication: 2014 CONFERENCE NAME 96th Annual Meeting and Expo of the Endocrine Society, ENDO 2014 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2014-06-21 to 2014-06-24 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), has shown promising therapeutic effects for the treatment of metastatic melanoma and other malignancies. Compared with conventional chemotherapy, the adverse effects are unique. Ipilimumab-related endocrinopathies have been reported in clinical trials and case reports. Hypophysitis is the most common endocrinopathy associated with anti-CTLA4 therapy. The incidence, time of onset after initiation of ipilimumab, and the reversal of the hypophysitis with or without high dose glucocorticoid treatment have not been well defined. We characterized 26 patients with metastatic melanoma who received ipilimumab treatment and developed immunotherapy-related hypophysitis. Hypophysitis was diagnosed by biochemical evidence of anterior pituitary hormone deficiency. Two-thirds of the patients (18/26) who developed ipilimumab-related hypophysitis were male. Fifty-eight percent (15/26) of the patients had MRI evidence of pituitary enlargement. Hyponatremia was identified in 54% (14/26) of patients. The median time of onset of hypophysitis was 9 weeks after initiation of ipilimumab therapy (range: 5-36 weeks). The rates of remission of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male hypogonadotropic hypogonadism (the majority of female patients were menopausal), and hyponatremia were 73%, 0%, 61%, 47%, and 93% respectively. The median times for resolution of pituitary enlargement, secondary hypothyroidism, male hypogonadotropic hypogonadism, and hyponatremia were 16, 11, 27.5, and 3.5 weeks, respectively. High dose glucocorticoid treatment did not increase the rate of resolution but appeared to shorten the time to resolution in male hypogonadotropic hypogonadism and secondary hypothyroidism. In conclusion, in this large case analysis, we have found that the time to onset is typically several weeks after initiation of therapy. Notably, hyponatremia is common among these patients. Although remission may occur in many of the immunotherapy-associated anterior pituitary hormone deficiency, secondary adrenal insufficiency did not remit in any cases. High dose glucocorticoid treatment did not alter the outcome of ipilimumab-associated hypophysitis. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 glucocorticoid hypophysis hormone monoclonal antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis immunotherapy metastatic melanoma society EMTREE MEDICAL INDEX TERMS adenohypophysis adrenal insufficiency adverse drug reaction case report chemotherapy clinical trial (topic) drug megadose endocrine disease female hormone deficiency human hypogonadotropic hypogonadism hyponatremia hypophysis hypothyroidism male nuclear magnetic resonance imaging patient remission therapy therapy effect LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72340013 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 107 TITLE A rare case of ipilimumab induced pituitary hypophysitis: An evolving clinical entity AUTHOR NAMES Buddhdev K. Buddhdev B.M. AUTHOR ADDRESSES (Buddhdev K.) Abington Memorial Hospital, Abington, United States. (Buddhdev B.M.) Cleveland Clinic, Cleveland, United States. CORRESPONDENCE ADDRESS K. Buddhdev, Abington Memorial Hospital, Abington, United States. SOURCE Endocrine Reviews (2014) 35 SUPPL. 3. Date of Publication: 2014 CONFERENCE NAME 96th Annual Meeting and Expo of the Endocrine Society, ENDO 2014 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2014-06-21 to 2014-06-24 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen- 4 (CTLA-4) recently approved for the treatment of metastatic melanoma; however a host of new side effects related to the mechanism of action of these drugs has appeared. Ipilimumab related adverse reactions are mainly autoimmune and occur in 61% of patients, of which 7.6% involve endocrinopathies like hypo and hyperthyroidism secondary to thyroiditis, primary adrenal insufficiency and isolated hypogonadism. We present an interesting case of Ipilimumab associated hypophysitis, which occurs in about 1.5% patients receiving this medication. Case report 68 year old Caucasian male presented to the emergency room with weakness, nausea, vomiting, diarrhea and headache since 1 week. His past medical history was significant for Stage IV spindle cell melanoma and hepatitis B. He was enrolled in an ipilimumab study and received 10 mg/kg dose for 3 cycles. Laboratory studies on admission were significant for sodium 124 mmol/L, serum free AM Cortisol 0.25 ug/dL, ACTH 1.0 pg/mL, TSH 0.24 uIU/mL and thyroxine 4.34 ug/dL. Magnetic resonance imaging of brain revealed no evidence of metastatic disease but instead showed enlargement of the pituitary gland of 12 mm in craniocaudal length and thickening of infundibulum with diffuse enhancement consistent with lymphocytic hypophysitis. Ipilimumab was stopped and he was started on tapering doses of prednisone 60 mg daily as well as levothyroxine 75 mcg daily. In contrast to the most patients who usually shows improvement within 1-2 weeks following discontinuation of ipilimumab, his symptoms recurred when steroids were tapered and required him to be on long term replacement therapy. Discussion Endocrinologists need to be aware of this new immuno-modulating agent used in cancer treatment as it causes a variety of autoimmune complications which could be life threatening if unrecognized. Pituitary hypophysitis is usually is associated with ipilimumab dose of 10mg/kg and after its third administration. Only MRI can make the diagnosis in some patients without clinical and/or biological signs. Disease is usually reversible after stopping the drug and may require hormonal supplementation. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticotropin cytotoxic T lymphocyte antigen 4 human monoclonal antibody hydrocortisone levothyroxine prednisone sodium steroid thyrotropin thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysis hypophysitis society EMTREE MEDICAL INDEX TERMS adrenal insufficiency adverse drug reaction brain cancer therapy case report Caucasian diagnosis diarrhea drug therapy emergency ward endocrinologist headache hepatitis human hyperthyroidism hypogonadism laboratory male medical history melanoma metastasis metastatic melanoma nausea nuclear magnetic resonance imaging patient serum side effect spindle cell substitution therapy supplementation thyroiditis vomiting weakness LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72340015 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 108 TITLE Serial TSH levels during treatment and onset of ipilimumab-induced hypophysitis. Failure of TSH alone to make the diagnosis AUTHOR NAMES Alkhaddo J.B. Khowaja A. Saeed A. Burmeister L. AUTHOR ADDRESSES (Alkhaddo J.B.; Khowaja A.; Saeed A.) University of Minnesota, Minneapolis, United States. (Burmeister L.) University of Minnesota Medical Center, Minneapolis, United States. CORRESPONDENCE ADDRESS J.B. Alkhaddo, University of Minnesota, Minneapolis, United States. SOURCE Endocrine Reviews (2014) 35 SUPPL. 3. Date of Publication: 2014 CONFERENCE NAME 96th Annual Meeting and Expo of the Endocrine Society, ENDO 2014 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2014-06-21 to 2014-06-24 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introducion Ipilimumab, a monoclonal antibody directed against CTLA-4 receptors, enhances host immune response against tumor cells and has been used to treat metastatic malignant melanoma. Its use has been associated with immune-related adverse events including hypophysitis and other hormone abnormalities. The drug package inserts recommends to monitor thyroid function tests before each dose during ipilimumab therapy. We present a case of a 53 y/o woman treated with Ipilimumab who presented with hyponatremia in association with adrenal insufficiency and hypothyroidism. The onset of central hypothyroidism correlated with low TSH, but was not diagnosed until hyponatremia presented and low free T4 was measured. Case A 53 year old woman was diagnosed in 2000 with a melanoma on the plantar foot. CT chest in 2012, incidentally discovered right sided pulmonary nodules, later proven to be metastatic malignant melanoma. She underwent six cycles of interleukin-2 treatment followed by radiation therapy. Follow up imaging showed disease progression. Therapy was changed to Ipilimumab 3 mg/kg every 3 weeks for a total of 4 cycles. Less than 7 weeks after the last dose of ipilimumab, she presented with 2-3 weeks of fatigue, dizziness, cold intolerance, dry skin, memory impairment and headaches. Labs showed hyponatremia (Na 118 mM (133-144), Urine osm 431 mmol/kg, urine Na 87 mM) and other labs were consistent with hypopituitarism: Cortisol 0.7 ug/dL (4-22), free T4 0.45 ng/dL (0.7- 1.85), TSH 1.49 mU/L (0.4-5), IGF1 44 ng/ml (83-242), FSH 5.4 IU/L (23-116) LH 0.7 IU/L (16- 54). Central hypothyroidism and hypoadrenalism due to presumed hypophysitis was treated with levothyroxine and high doses of methylprednisolone and later prednisone. Pituitary MRI 3 days after hyponatremia presentation was normal. Hyponatremia improved with intravenous normal saline infusion and the above therapy. Follow up labs, 2 months later, showed improvement of thyroid function, but not of the pituitary-adrenal function. Serial TSH measurements during ipilipumab therapy had not resulted in identification of central hypothyroidism prior to the presentation with hyponatremia: TSH 5.85 (before ipilimumab); TSH on ipilimumab 3.24 (day 1 ), 3.47 (day 22), 5.55 (day 43, with free T4 0.98), 4.01 (day 60). One week prior to presentation with hyponatremia the TSH was 0.13 mU/L and brain MRI suggested a change in the pituitary gland (now convex upward upper border, identified in retrospect) compared to one year earlier. Conclusion This case illustrates how even with a high index of suspicion, the diagnosis of hypophysitis with ipilimumab therapy can be missed at earliest presentation, especially if thyroid function testing is incomplete. Free T4 should be added to TSH for hypothyroid screening in patients getting ipilimumab, and more specific guidelines for oncologists should be emphasized. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab thyrotropin EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 follitropin hormone hydrocortisone interleukin 2 levothyroxine methylprednisolone monoclonal antibody prednisone receptor sodium chloride EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) diagnosis hypophysitis society EMTREE MEDICAL INDEX TERMS adrenal insufficiency brain disease course dizziness drug megadose drug packaging dry skin fatigue female follow up headache human hyponatremia hypophysis hypophysis adrenal system hypopituitarism hypothyroidism imaging immune response infusion lung nodule melanoma memory disorder nuclear magnetic resonance imaging oncologist patient radiotherapy screening therapy thorax thyroid function thyroid function test tumor cell urine LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72340014 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 109 TITLE Ipilimumab-induced hypophysitis: A detailed longitudinal analysis in a large cohort of patients with metastatic melanoma AUTHOR NAMES Faje A.T. Sullivan R. Lawrence D. Tritos N.A. Klibanski A. Nachtigall L.B. AUTHOR ADDRESSES (Faje A.T.) Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States. (Sullivan R.; Lawrence D.) Massachusetts General Hospital, Boston, United States. (Tritos N.A.; Klibanski A.; Nachtigall L.B.) Massachusetts General Hospital, Harvard Medical School, Boston, United States. CORRESPONDENCE ADDRESS A.T. Faje, Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States. SOURCE Endocrine Reviews (2014) 35 SUPPL. 3. Date of Publication: 2014 CONFERENCE NAME 96th Annual Meeting and Expo of the Endocrine Society, ENDO 2014 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2014-06-21 to 2014-06-24 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Ipilimumab (ipi) is a monoclonal antibody approved for the treatment of unresectable or metastatic melanoma. Ongoing studies are evaluating ipi and other new immunotherapeutic agents to treat various malignancies. Relatively little is known about ipilimumab-induced hypophysitis (IH), an important treatment complication. Objective: To (1) examine the incidence of IH, (2) characterize the clinical course and treatment outcomes in patients with IH, (3) identify risk factors for the development of IH, and (4) determine optimal strategies for the management of IH. Design and Methods: 154 patients with metastatic melanoma were evaluated at the Massachusetts General Hospital and treated with ipi between 3/2008 and 12/2013. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were analyzed. Results: IH was diagnosed in 17 patients (11% of the cohort). Male gender and age were risk factors for the development of IH (IH prevalence in males 15.5% vs 3.6% in females, p=0.02; mean age 68.2 ± 2.4 vs 59.9±1.0 years, p=0.005 in IH vs patients without IH). The incidence of IH was not related to the cumulative dose of ipi (mean number of ipi cycles 3.06±0.18 vs 3.72±0.23, p=0.27 in IH vs patients without IH). All patients with IH had anterior hypopituitarism; none had diabetes insipidus. Most patients (14/17) had multiple pituitary hormone deficiencies. Diffuse pituitary enlargement was observed in all cases of IH and, upon retrospective review of MRI's, this finding preceded the diagnosis of hypophysitis in 8 patients. The degree of pituitary enlargement was mild; optic chiasm compression did not occur in any patient. Pituitary enlargement was not observed in patients without IH. The majority of patients (81%) with IH had persistent hypopituitarism. Recovery of adrenal function was demonstrated in one patient, thyroid recovery occurred in one patient, and gonadal function normalized in two patients. Radiographic resolution of pituitary enlargement was observed in all patients with IH, and it occurred rapidly (resolution was observed in 7/7 patients within 40 days of the diagnosis of IH). The median length of survival in patients with IH was 19.4 vs 8.8 months in the remainder of the cohort. The difference in survival between the two groups was borderline significant (p=0.05). Conclusions: Patients treated with ipilimumab have a substantial risk of hypophysitis which is higher in men and older patients. Pituitary enlargement appears to be pathognomonic for ipilimumab-induced hypophysitis, can precede the clinical diagnosis, and resolves rapidly. Recovery of anterior pituitary function is rare. The incidence of hypophysitis may be a positive predictor for survival in melanoma patients treated with ipilimumab. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS hypophysis hormone immunomodulating agent monoclonal antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) human hypophysitis metastatic melanoma patient society EMTREE MEDICAL INDEX TERMS adenohypophysis adrenal function compression diabetes insipidus diagnosis disease course drug therapy female gender general hospital gonad function hormone deficiency hypophysis hypophysis function hypopituitarism laboratory male medical record melanoma nuclear magnetic resonance imaging optic chiasm prevalence risk risk factor survival thyroid gland treatment outcome United States LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72340012 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 110 TITLE Thyroid dysfunction in a patient treated with ipilimumab: Autoimmune thyroid disease associated with anti-CTLA-4 therapy AUTHOR NAMES Krull I. Rogowski-Lehmann N. Sigrist S. Siano M. Brändle M. Bilz S. AUTHOR ADDRESSES (Krull I.; Rogowski-Lehmann N.; Sigrist S.; Siano M.; Brändle M.; Bilz S.) Cantonal Hospital St. Gallen, Switzerland. CORRESPONDENCE ADDRESS I. Krull, Cantonal Hospital St. Gallen, Switzerland. SOURCE Endocrine Reviews (2014) 35 SUPPL. 3. Date of Publication: 2014 CONFERENCE NAME 96th Annual Meeting and Expo of the Endocrine Society, ENDO 2014 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2014-06-21 to 2014-06-24 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction Ipilimumab (IPI), a cytotoxic-T-lymphocyte-associated antigen-4 (CTLA-4) antibody, has been the first agent to demonstrate an overall survival benefit for metastatic melanoma through increased T-cell activation. Various immune-mediated adverse events, among them gastrointestinal and dermatologic being most frequent, have been reported. Hypophysitis, leading to pan- or partial hypopituitarism, thyroid and primary adrenal dysfunction may occur and lead to significant morbidity if not recognised and properly managed. Case report A 66-year-old man who had been treated with two cycles of IPI was referred because of newonset overt hyperthyroidism (free thyroxine 54 pmol/l). Thyroid function had been normal prior to therapy. The diagnosis of Graves' disease was established based on increased TSH receptor antibodies and diffuse hyperperfusion of the thyroid gland on colour-flow ultrasonography. Carbimazole 10 mg t.i.d. was started and rapidly tapered to 5 mg q.d. because of rapid clinical and biochemical resolution. However, overt hypothyroidism developed despite stopping antithyroid drug therapy and thyroxine treatment became necessary 8 weeks after the initial presentation and a total of 4 cycles of IPI. The TSH receptor antibody titer further increased at this time and increased thyroid peroxidase antibodies were detected. TSH receptor antibodies and hypothyroidism persisted 6 months after the last IPI treatment and the patient remained euthyroid on thyroxine therapy. Conclusion Hypothyroidism may occur in up to 3 % of patients treated with IPI. Graves' disease is less frequently observed and only 3 cases have been reported in the literature. The rapid onset of hypothyroidism despite tapering and finally stopping antithyroid drug therapy and the increase of the TSH receptor antibody titer suggests a switch from stimulating to blocking antibodies. Whether the immune mediated thyroid dysfunction following IPI is reversible remains to be established. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) cytotoxic T lymphocyte antigen 4 ipilimumab EMTREE DRUG INDEX TERMS antibody antithyroid agent blocking antibody carbimazole thyroid peroxidase antibody thyrotropin thyrotropin receptor antibody thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) autoimmune thyroiditis human patient society therapy thyroid disease EMTREE MEDICAL INDEX TERMS adrenal disease antibody titer case report color diagnosis drug therapy echography free thyroxine index Graves disease hyperthyroidism hypophysitis hypopituitarism hypothyroidism male metastatic melanoma morbidity overall survival T lymphocyte activation thyroid function thyroid gland LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72339444 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 111 TITLE A case of pituitary failure following treatment with ipilimumab AUTHOR NAMES Gill P.M. Story E.S. AUTHOR ADDRESSES (Gill P.M.; Story E.S.) Carolinas Medical Center, Charlotte, United States. (Story E.S.) Levine Cancer Institute, Charlotte, United States. CORRESPONDENCE ADDRESS P.M. Gill, Carolinas Medical Center, Charlotte, United States. SOURCE Journal of General Internal Medicine (2016) 31:2 SUPPL. 1 (S493-S494). Date of Publication: May 2016 CONFERENCE NAME 39th Annual Meeting of the Society of General Internal Medicine, SGIM 2016 CONFERENCE LOCATION Hollywood, FL, United States CONFERENCE DATE 2016-05-11 to 2016-05-14 ISSN 1525-1497 BOOK PUBLISHER Springer New York LLC ABSTRACT LEARNING OBJECTIVE #1: Recognize lymphocytic hypophysitis as a toxicity from immune checkpoint therapy. LEARNING OBJECTIVE #2: Describe the diagnostic criteria and management of the initial presentation of lymphocytic hypophysitis. CASE: RL is a 59 year old male with a past medical history of stage IV metastatic melanoma without evidence of intracranial metastasis, newly diagnosed hypothyroidism, and coronary artery disease who presented following a syncopal event. He denied any orthostatic or preceding symptoms but his wife did endorse a low blood pressure following the event. RL's metastatic melanoma was undergoing treatment with dabrafenib and trametinib. He was then started on ipilimumab in addition to his other treatments 10 weeks prior to the event. Over time, he started to endorse fatigue, constipation, and a persistent frontal headache. RL was hypotensive on arrival to the emergency room and despite aggressive fluid resuscitation, he remained hemodynamically unstable. His exam was unremarkable for infectious etiology and his neurologic exam was intact. A thorough infectious workup, including a lumbar puncture, was performed and unrevealing. He was started on hydrocortisone with rapid improvement in his hemodynamics. MRI brain with gadolinium and thin pituitary cuts was performed which showed enlargement of the pituitary gland consistent with hypophysitis. Subsequent studies identified central hypothyroidism and hypogonadotropic hypogonadism. He was started on hormone replacement therapies with improvement of his symptoms. DISCUSSION: Lymphocytic hypophysitis is an autoimmune process resulting in inflammation of the pituitary gland that can lead to hypopituitarism. Extreme cases, if left untreated, can result in death due to adrenal crisis, characterized by electrolyte abnormalities and severe hypotension. Classic cases of lymphocytic hypophysitis will present with fatigue and a frontal headache, which can be debilitating. Common associated symptoms also include nausea and visual field defects. Given the non-specific nature of the majority of symptoms, they may be missed unless careful vigilance is undertaken. Chart review for RL showed that he had complained of his headache and fatigue for approximately 2 months prior to presenting with adrenal insufficiency. Typical cases of lymphocytic hypophysitis result in central hypothyroidism and secondary adrenal insufficiency. It is essential to obtain a free T4 as TSH may be within normal limits in cases of central hypothyroidism. ACTH stimulation testing may be normal in the setting of acute pituitary failure as the adrenal gland has not had time to atrophy. MRI with and without contrast will further support the diagnosis by demonstrating enlargement of the pituitary gland; however, it is essential to obtain thin cuts through the pituitary as it could be missed with routineMRI brain protocols. All of these provide barriers to diagnosis, demonstrating how a strong clinical suspicion is important for prompt diagnosis. RL was diagnosed with lymphocytic hypophysitis secondary to his ipilimumab therapy. This disorder, which was once almost exclusive to young pregnant females, is increasing in prevalence with the usage of immune checkpoint therapies (i.e. anti-CTLA-4 and anti-PD-1 agents). Most studies report a 1-2 % occurrence of hypophysitis with these treatments, however, this is likely underreported due to a lack of recognition of more indolent presentations. Some studies suggest that the true prevalence may be has high as 10 % following these treatments. Immune checkpoint therapy is growing in prevalence for the treatment of metastatic melanoma, small cell lung cancer, and renal cell carcinoma, providing patients with another treatment option with promising results. These drugs, however, have a unique set of toxicities and adverse effects. General internists will often be the first to hear about these symptoms as they seem non-specific and potentially unrelated to their immunotherapy. Prompt recognition can promote an improved quality of life and prevent a life threatening adrenal crisis. There are no studied treatment regimens at this time; however, there are suggestions available based on expert opinion. Initial treatments include with holding the offending agent and starting high dose steroids, which treat both hypophysitis and hemodynamic compromise, if it is present. A prolonged steroid taper is performed with close monitoring for return of symptoms, primarily headache and visual field defects, as recurrence of hypophyitis is common during the taper. With adequate treatment, enlargement of the pituitary gland will typically resolve, while return of pituitary function is much less likely. Case series estimate return of function in only 37- 50 % of patients. Therefore, while glucocorticoid replacement is initiated, a full investigation of the hypothalamic pituitary axis should be performed, adequately replaced, and followed longitudinally. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS antihypertensive agent corticotropin cytotoxic T lymphocyte antigen 4 dabrafenib electrolyte gadolinium glucocorticoid hydrocortisone steroid thyrotropin trametinib EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypopituitarism internal medicine society EMTREE MEDICAL INDEX TERMS adrenal cortex insufficiency adrenal gland adrenal insufficiency adverse drug reaction alertness atrophy brain case study constipation coronary artery disease death diagnosis diseases drug megadose emergency ward etiology fatigue female fluid resuscitation headache hemodynamics hormone substitution human hypogonadotropic hypogonadism hypophysis hypophysis function hypophysitis hypotension hypothalamus hypophysis system hypothyroidism immunotherapy inflammation internist kidney carcinoma lumbar puncture male medical history medical record review metastasis metastatic melanoma monitoring nausea nuclear magnetic resonance imaging patient prevalence quality of life small cell lung cancer stimulation therapy toxicity visual field defect LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72288879 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 112 TITLE Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab AUTHOR NAMES Eatrides J.M. Weber J. Egan K. Acierno M. Schell M. Lillienfeld H. Creelan B. AUTHOR ADDRESSES (Eatrides J.M.) University of South Florida, Tampa, United States. (Weber J.; Egan K.; Acierno M.; Schell M.; Lillienfeld H.; Creelan B.) Moffitt Cancer Center, Tampa, United States. CORRESPONDENCE ADDRESS J.M. Eatrides, University of South Florida, Tampa, United States. SOURCE Cancer Research (2015) 75:14 SUPPL. 1. Date of Publication: 15 Jul 2015 CONFERENCE NAME AACR Special Conference on Advances in Melanoma: From Biology to Therapy 2014 CONFERENCE LOCATION Philadelphia, PA, United States CONFERENCE DATE 2014-09-20 to 2014-09-23 ISSN 0008-5472 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Introduction: Autoimmune hypophysitis (AH) is an immune-related adverse effect (ir-AE) of the human IgG1 monoclonal antibody ipilimumab. Evidence suggests AH is mediated by complement deposition in adenohypophyseal cells expressing cytotoxic T lymphocyte antigen-4 (CTLA-4). Despite increasing incidence, AH remains poorly characterized. We conducted a retrospective cohort study of melanoma subjects treated with ipilimumab, with the primary objective to characterize AH and examine its association with overall survival (OS). Methods: Inclusion criteria: stage 3/4 cutaneous, ocular, or mucosal melanoma at a single institution, treated with ipilimumab between 2005 and 2013. AH was defined as primary hypopituitarism clinically diagnosed by endocrinologist or cutaneous oncologist. Baseline BMI and laboratory values were collected within 30 days prior to first dose. Overall survival (OS) was defined as time from first dose to death of any cause. Time-to-progression (TTP) was defined as time from first dose to any objective progression event, and censored if >4 months (mo) elapsed between evaluations to ensure homogenous follow-up time. Statistical tests were non-parametric and 2-sided. Results: Of 295 patients screened, 269 were eligible (32 AH+, 237 AH-). Demographics at first dose: median age 61.6, 35% female, 99.3% white, 1.9% Hispanic, mean body mass index (BMI) 28 kg/m2, mean lactate dehydrogenase (LDH) 644 IU/L, mean albumin 4.0 mg/dL, mean absolute lymphocyte count 1.39 x 103/μL. For TNM stage, 65% M1c, 14% M1b, 6% M1a, 15% M0. At time of first dose, 29.5% were resected no evidence-of-disease (NED). Of 132 (49%) with known allelic status, 38 (29%) were BRAF mutant. Median time-to-AH was 2.8 mo (range 0.9 - 18.7). Initial dose of 10 mg/kg was associated with increased AH risk (RR 1.2, p=0.002). Presenting symptoms included fatigue (58%), headache (33%), nausea (24%). Lab findings at diagnosis (median, range): ACTH 7.0 (1-26), cortisol 2.2 (0-29.7), TSH 0.34 (0-3.9), T4 0.7 (0.3 - 3.6), FSH 7.0 (1.1 - 41), LH 0.7 (0.2 - 20.5). 17 of 30 evaluable subjects had abnormal pituitary identified on MRI. All were administered exogenous corticosteroids and 72% required exogenous thyroid supplementation. 13% eventually recovered endogenous pituitary function. There was no association with prior endocrine conditions or other ir-AEs. For evaluable subjects, AH also seemed to have favorable objective response rate, although this was not statistically significant (p=0.20). Median follow-up duration was 43.7 mo, median OS was 20.3 mo, and median TTP was 5.2 mo. AH was associated with superior OS (HR 0.4, 95% CI 0.3 - 0.7, p=0.001) and TTP (HR 0.4, 95%CI 0.3- 0.8, p=0.0002). Using Landmark analysis to avoid bias from immortal person-time, after 4 cycles of ipilimumab, AH remained associated with OS (HR 0.5, p=0.04). Using the alternative Crowley method, similar results were seen for both OS (HR 0.5, p=0.002) and TTP (HR 0.6, p=0.005). AH was then examined as a time-dependent covariate in Cox regression. On univariate analysis, LDH, M-stage, resected NED, albumin, age, absolute lymphocyte count, and AH were significantly associated with OS (p <0.01 for all). Similar findings were found for TTP. After including a propensity score regression term to control for all known confounders (LDH, albumin, BMI, lymphocyte count, M-stage, NED, smoking, race, age, gender), AH remained an independent predictor for improved OS (HR 0.49;95%CI 0.24-0.98; p=0.04). Conclusion: Hypophysitis appears to predict benefit from ipilimumab treatment, possibly since it may serve as a marker of cellular immune activation. Independent validation of these results in external cohorts is required. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab marker EMTREE DRUG INDEX TERMS albumin corticosteroid corticotropin cytotoxic T lymphocyte antigen 4 follitropin hydrocortisone lactate dehydrogenase monoclonal antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis melanoma therapy EMTREE MEDICAL INDEX TERMS adverse drug reaction body mass cohort analysis complement deposition death diagnosis endocrinologist fatigue female follow up gender headache Hispanic human hypophysis hypophysis function hypopituitarism laboratory lymphocyte count mucosal melanoma mutant nausea nuclear magnetic resonance imaging oncologist overall survival patient propensity score proportional hazards model risk smoking supplementation thyroid gland univariate analysis LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72208942 DOI 10.1158/1538-7445.MEL2014-B23 FULL TEXT LINK http://dx.doi.org/10.1158/1538-7445.MEL2014-B23 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 113 TITLE Risk of endocrine complications and elevated liver transaminases in patients with solid tumors treated with immune checkpoint inhibitors; A meta-analysis AUTHOR NAMES Elhalawani H. Fouad M. Abdel-Rahman O.M. AUTHOR ADDRESSES (Elhalawani H.; Abdel-Rahman O.M.) Clinical Oncology, Ain Shams University Hospital, Cairo, Egypt. (Fouad M.) Medical Microbiology and Immunology Department, Ain Shams University, Faculty of Medicine, Cairo, Egypt. CORRESPONDENCE ADDRESS H. Elhalawani, Clinical Oncology, Ain Shams University Hospital, Cairo, Egypt. SOURCE Annals of Oncology (2015) 26 SUPPL. 8 (viii8). Date of Publication: November 2015 CONFERENCE NAME ESMO Symposium on Immuno-Oncology 2015 CONFERENCE LOCATION Lausanne, Switzerland CONFERENCE DATE 2015-11-20 to 2015-11-21 ISSN 0923-7534 BOOK PUBLISHER Oxford University Press ABSTRACT Aim: The feasibility and efficacy of immune checkpoint inhibitors for patients with advanced malignancies have been tackled in numerous trials in the past few years. We performed a systematic review and meta-analysis of the risk of endocrine adverse events, along with the incidence of elevated liver transaminases, associated with immune checkpoint inhibitors. Methods: Eligible studies included randomized phase II and III trials of patients with solid tumors on ipilimumab, nivolumab, pembrolizumab, tremelimumab and pidilizumab; describing events of hypothyroidism, hyperthyroidism, hypopituitarism/hypophysitis and adrenal insufficiency; in addition to events of elevated liver transaminases [alanine aminotransferase (ALT) and aspartate amintransferase (AST)]. Results: Our search strategy yielded 210 potentially relevant citations on immune checkpoint inhibitors from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 10 clinical trials evaluating ipilimumab, nivolumab, tremelimumab and pembrolizumab were considered eligible for the meta-analysis. The RR of all-grade hypothyroidism, hyperthyroidism, hypophyisitis and adrenal insufficiency were 8.26 (95% CI : 4.67-14.62; p < 0.00001), 5.48 (95% CI: 1.33-22.53; p = 0.02); 22.03 (95% CI: 8.52-56.94; p < 0.00001), 3.87 (95% CI: 1.12-13.41; p =0.03) respectively. Whereas, the RR of all grade elevated ALT and AST was 2.29 (95% CI 1.14-4.62; p < 0.0001) and 1.5 (95% CI: 0.69-3.29; p = 0.31) respectively. While for high grade elevated ALT and AST, it was 9.42 (95% CI: 4.31-20.6; p < 0.0001) and 10.65 (95% CI: 4.16-27.27; p < 0.0001) respectively. Conclusions: Our meta-analysis has demonstrated that the use of immune checkpoint inhibitors is associated with an increased risk of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency compared to control. Moreover, the use of immune checkpoint inhibitors has a causal relationship to an increased risk of high grade elevated ALT and AST. Clinicians should be aware of these risks and perform regular monitoring. EMTREE DRUG INDEX TERMS alanine aminotransferase aspartic acid ipilimumab nivolumab pembrolizumab pidilizumab ticilimumab EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) human hypertransaminasemia meta analysis oncology patient risk solid malignant neoplasm EMTREE MEDICAL INDEX TERMS adrenal insufficiency clinical trial (topic) hyperthyroidism hypophysitis hypothyroidism library monitoring register systematic review LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72202870 DOI 10.1093/annonc/mdv514.11 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdv514.11 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 114 TITLE MEK inhibition enhances immune checkpoint blockade treatment of murine models of neuroblastoma AUTHOR NAMES Muthugounder S. Hung L. Chan R. Kim J. Shirinbak S. Shimada H. Asgharzadeh S. AUTHOR ADDRESSES (Muthugounder S.; Hung L.; Kim J.; Shirinbak S.; Shimada H.; Asgharzadeh S.) USC/Children's Hospital Los Angeles, Los Angeles, United States. (Chan R.) USC, Los Angeles, United States. CORRESPONDENCE ADDRESS S. Muthugounder, USC/Children's Hospital Los Angeles, Los Angeles, United States. SOURCE Cancer Research (2015) 75:15 SUPPL. 1. Date of Publication: 1 Aug 2015 CONFERENCE NAME 106th Annual Meeting of the American Association for Cancer Research, AACR 2015 CONFERENCE LOCATION Philadelphia, PA, United States CONFERENCE DATE 2015-04-18 to 2015-04-22 ISSN 0008-5472 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Background: The tumor microenvironment (TME) plays an important role in neuroblastoma (NBL) biology. Infiltrations of tumor-associated macrophages with alterations in patterns of pro-inflammatory genes are associated with poor prognosis in NBL. However, the role of regulatory T-cells in NBL remains unknown. As several genes in MAPK pathway are among recurrent mutations in neuroblastomas, and the production of pro-inflammatory mediators in immune cells is MAPK-dependent, we hypothesized targeted kinase inhibitor in combination with check-point blockade could exert synergistic effects on the TME's response to tumor cells. Therefore, we assessed the efficacy of combined therapy using a transgenic MYCN non-amplified neuroblastoma murine model driven by SV40 large T antigen (NB-Tag). Methods: Three human neuroblastoma cell lines and two NB-Tag derived mouse cell-lines were used for in vitro cell proliferation assay. For in vivo tumor growth models, combinations of cyclophosphamide, topotecan, trametinib, anti-CTLA4, and anti-PD1 therapies were studied in NB-Tag transgenic and transplantable subcutaneous (NB-SQ) murine models. Results: In vitro studies demonstrated trametinib had the highest anti-proliferative activity compared to other kinase inhibitors, and it effectively blocked cell cycle arrest in G1 phase. These anti-proliferative effects could not be rescued by co-culturing tumor cells with murine or human macrophages. In NB-Tag mice, which develop neuroblastoma spontaneously at 12 weeks, daily oral administration of trametinib (0.6mg/Kg) at pre-tumoral age (10 wk) significantly impaired tumor growth by 17 weeks (1424 mm(3) in controls vs. 43 mm3(3)in treated mice). Treatment of 15 week-old NB-Tag mice (visible tumor by MRI) with trametinib after chemotherapy administration (5-days of Cyclophosphamide + Topotecan) also significantly impaired tumor regrowth (volume four weeks post-chemo, 491 vs. 42 mm(3), p = 0.037), and more importantly, treatment increased the survival of NB-Tag mice compared to control (median survival: control = 24.5 wk, treated = 35 wk, p<0.0001). Trametinib treatment also showed similar results in the NB-SQ model. Addition of immune checkpoint blockade of NB-SQ mice with anti-CTLA4 and anti-PD1 to treatment with trametinib further increased survival compared to controls (p<0.0001). Tumors and macrophages collected from mice treated with trametinib showed effective block in phosphorylation of ERK. Transgenic animals that grew despite trametinib treatment showed strong STAT3 phosphorylation suggesting this pathway as an escape mechanism. Conclusions: Our results provide strong evidence that MEK inhibition combined with checkpoint blockade significantly inhibited tumor formation in a syngeneic subcutaneous model. These findings indicate opportunities to enhance antitumor immunity with the potential to produce durable clinical responses in children with neuroblastomas. EMTREE DRUG INDEX TERMS cyclophosphamide cytotoxic T lymphocyte antigen 4 minoxidil phosphotransferase inhibitor STAT3 protein topotecan trametinib virus large T antigen EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American cancer research murine model neuroblastoma EMTREE MEDICAL INDEX TERMS antiproliferative activity carcinogenesis cell cycle arrest cell line cell proliferation assay chemotherapy child coculture gene human immunity immunocompetent cell in vitro study macrophage model mouse mutation neoplasm neuroblastoma cell line nuclear magnetic resonance imaging oral drug administration phosphorylation prognosis regulatory T lymphocyte survival therapy transgenic animal tumor associated leukocyte tumor cell tumor growth tumor microenvironment LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72190999 DOI 10.1158/1538-7445.AM2015-400 FULL TEXT LINK http://dx.doi.org/10.1158/1538-7445.AM2015-400 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 115 TITLE Case series of thyroid dysfunction induced by nivolumab (anti-PD-1; ono-4538) AUTHOR NAMES Tanaka R. Fujisawa Y. Maruyama H. Nakamura Y. Yoshino K. Ohtsuka M. Fujimoto M. AUTHOR ADDRESSES (Tanaka R.; Fujisawa Y.) University of Tsukuba, Tsukuba, Japan. (Maruyama H.; Fujimoto M.) Department of Dermatology, University of Tsukuba, Ibaraki, Japan. (Nakamura Y.) Department of Skin Oncology/Dermatology, Saitama Medical University, International Medical Center, Saitama, Japan. (Yoshino K.) Department of Dermatology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan. (Ohtsuka M.) Department of Dermatology, Fukushima Medical University, School of Medicine, Fukushima, Japan. CORRESPONDENCE ADDRESS R. Tanaka, University of Tsukuba, Tsukuba, Japan. SOURCE Annals of Oncology (2015) 26 SUPPL. 2 (ii34-ii35). Date of Publication: March 2015 CONFERENCE NAME 13th International Congress on Targeted Anticancer Therapies, TAT 2015 CONFERENCE LOCATION Paris, France CONFERENCE DATE 2015-03-02 to 2015-03-04 ISSN 0923-7534 BOOK PUBLISHER Oxford University Press ABSTRACT Background: Nivolumab, a PD1-specific monoclonal antibody, was approved in Japan on July 2014 for patients with unresectable or metastatic melanoma. Patients: Nivolumab at 2 mg/kg every 3 weeks were initiated to 18 patients with unresectable or metastatic melanoma at University of Tsukuba Hospital. The median age was 71 (range, 39-80) and male:female ratio was 8:10. Of those, 15 patients had primary site at skin and the other 3 had at mucosa. Most of the patients was performance status (PS) score 0 or 1, except 1 patient with PS score 2. Results: Seventeen adverse events (AE) were recorded. Most common AE was thyroid dysfunction and observed in 5 (28%); hyperthyroidism in 2 and hypothyroidism in 3. Whereas no one with hyperthyroidism required treatment, 2 out of 3 with hypothyroidism were symptomatic, such as fatigue and gain weight. However, their symptoms were recovered by replacement of thyroid hormone. No patient required discontinuation of nivolumab due to AEs. Conclusion: According to our study population, using nivolumab was generally safe. Because most of AEs were mild and were manageable, nivolumab seems to be safer than Ipilimumab. However, we should keep in mind that nivolumab might induce thyroid dysfunction. Patients with symptomatic hypothyroidism required hormone replacement therapy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS ipilimumab monoclonal antibody thyroid hormone EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) case study therapy thyroid disease EMTREE MEDICAL INDEX TERMS fatigue female hormone substitution hospital human hyperthyroidism hypothyroidism Japan male metastatic melanoma mucosa patient population skin university weight LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72187287 DOI 10.1093/annonc/mdv097.8 FULL TEXT LINK http://dx.doi.org/10.1093/annonc/mdv097.8 COPYRIGHT Copyright 2016 Elsevier B.V., All rights reserved. RECORD 116 TITLE Hyperthyroidism followed by worsening primary hypothyroidism in a patient treated with ipilimumab and pembrolizumab AUTHOR NAMES Batacchi Z. Alarcon-Casas Wright L. AUTHOR ADDRESSES (Batacchi Z.; Alarcon-Casas Wright L.) Division of Endocrinology, Metabolism and Nutrition, University of Washington, Seattle, United States. CORRESPONDENCE ADDRESS Z. Batacchi, Division of Endocrinology, Metabolism and Nutrition, University of Washington, Seattle, United States. SOURCE Thyroid (2015) 25 SUPPL. 1 (A215). Date of Publication: 2015 CONFERENCE NAME 15th International Thyroid Congress and 85th Annual Meeting of the American Thyroid Association CONFERENCE LOCATION Lake Buena Vista, FL, United States CONFERENCE DATE 2015-10-18 to 2015-10-23 ISSN 1050-7256 BOOK PUBLISHER Mary Ann Liebert Inc. ABSTRACT Ipilimumab and Pembrolizumab are immunostimulatory agents used to treat metastatic melanoma. Ipilimumab is a monoclonal antibody which binds to the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4 ) and Pembrolizumab is a monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells. Thyroid dysfunction may ensue as immune-related adverse effects of these medications. 55 year old man with a history of metastatic scalp melanoma, type 2 diabetes mellitus and primary hypothyroidism diagnosed 6 years ago with positive thyroid peroxidase antibodies. He had been stable on the same dose of levothyroxine 75mcg daily since diagnosis. Ipilimumab was commenced for treatment ofmelanoma. Prior to the first dose, TSH was 4.597 (0.400-5.00microIU/mL) and total T4 was 8.0 (4.8- 10.8mcg/dL). Three of four planned doses of Ipilimumab were given before he developed headache and fatigue. Investigations revealed hypophysitis (central adrenal insufficiency, central hypogonadism) and hyperthyroidism. Brain magnetic resonance imaging revealed an enlarged pituitary gland compared to prior exams. TSH was low on 2 occasions with elevated total T4 and Free T4 on two occasions. Ipilimumab was discontinued and within 3 weeks, his thyroid function tests improved: TSH 0.554 (0.400-5.00microIU/mL) and total T4 of 10.7 (0.400-5.00microIU/mL). He continued levothyroxine 75mcg daily. Four months later Pembrolizumab was initiated. He has received 6 doses in the last 4 months. His TSH has reproducibly and progressively increased, most recently 20.353 (0.400-5.00microIU/mL), despite increasing the dose of levothyroxine. The case describes a patient with baseline primary hypothyroidism who developed opposing effects in thyroid function after consecutive use of the immune check-point inhibitors Ipilimumab and Pembrolizumab. Individually, the immune-related adverse effects of these drugs upon the thyroid are uncommon and, to the best of our knowledge, have not been reported as sequential effects in one patient. This underscores the importance of close monitoring of thyroid function during treatment with these agents. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab pembrolizumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 levothyroxine monoclonal antibody receptor thyroid peroxidase antibody thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American human hyperthyroidism hypothyroidism patient thyroid gland EMTREE MEDICAL INDEX TERMS adrenal insufficiency adverse drug reaction apoptosis brain diagnosis drug therapy fatigue headache hypogonadism hypophysis hypophysitis male melanoma metastatic melanoma monitoring non insulin dependent diabetes mellitus nuclear magnetic resonance imaging scalp T lymphocyte thyroid disease thyroid function thyroid function test LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72066062 DOI 10.1089/thy.2015.29004.abstracts FULL TEXT LINK http://dx.doi.org/10.1089/thy.2015.29004.abstracts COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 117 TITLE Immune therapies targeting the thyroid: New insights from a comprehensive review of pembrolizumab-induced thyroiditis cases at mayo clinic AUTHOR NAMES Delivanis D. Merten M.M. Kottschade L. Ryder M. AUTHOR ADDRESSES (Delivanis D.; Merten M.M.; Ryder M.) Endocrinology, Mayo Clinic Rochester, Rochester, United States. (Kottschade L.) Oncology, Mayo Clinic, Rochester, Rochester, United States. CORRESPONDENCE ADDRESS D. Delivanis, Endocrinology, Mayo Clinic Rochester, Rochester, United States. SOURCE Thyroid (2015) 25 SUPPL. 1 (A38). Date of Publication: 2015 CONFERENCE NAME 15th International Thyroid Congress and 85th Annual Meeting of the American Thyroid Association CONFERENCE LOCATION Lake Buena Vista, FL, United States CONFERENCE DATE 2015-10-18 to 2015-10-23 ISSN 1050-7256 BOOK PUBLISHER Mary Ann Liebert Inc. ABSTRACT Immune checkpoint inhibitors ipilimumab, pembrolizumab and nivolumab induce potent anti-tumor responses and immune-related adverse effects (irAEs). Understanding irAEs is required to improve patient care and to enhance our knowledge of both rare and common autoimmune diseases, such as lymphocytic hypophysitis and Hashimoto's thyroiditis. The goal of this study was to comprehensively characterize pembrolizumab-induced thyroid dysfunction and examine its potential pathophysiology. We performed a retrospective review of cancer patients receiving pembrolizumab at Mayo Clinic from April 2014 till January 2015. Cases with abnormal thyroid function tests (TFTs) were further examined to determine etiology, incidence and clinical presentation of thyroid disorders. Of 92 patients receiving pembrolizumab (61% male, 39 % female), 13 (14%) developed abnormal TFTs with a median onset of 4 weeks. Of these, 10 (11%) represented new onset acute thyroiditis (n = 6, 2 female) and/or new hypothyroidism (n = 4, 1 female) while 3 (all female) represented recurrent hypothyroidism on thyroid hormone replacement. Nearly all patients (n = 12) received ipilimumab. Anti-thyroid peroxidase antibodies (anti-TPO), available in 10 cases, were elevated in 0 cases of thyroiditis, 2 cases of new onset hypothyroidism and 3 cases of recurrent hypothyroidism. On PET/CT, new thyroid fluorodeoxyglucose (FDG) uptake was identified in 6 of 13 cases with no correlation to anti-TPO status. Resolution of thyroiditis occurred in 2, progressed to hypothyroidism in 3 and was persistent in 1. One new onset hypothyroid patient had spontaneous thyroid function recovery. Combination immune checkpoint blockade enhances the incidence of thyroiditis/hypothyroidism compared to ipilimumab alone. Only 50% of patients developed elevated anti-TPO antibodies, suggesting autoantibody dependent and independent mechanisms. Ongoing studies are underway to better understand its pathophysiology in order to improve clinical care. Paradoxically, this knowledge may be used to induce anti-thyroid responses in patients with therapeutically refractory metastatic differentiated thyroid cancer. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS antibody autoantibody fluorodeoxyglucose ipilimumab nivolumab thyroid hormone thyroid peroxidase antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American hospital human immunotherapy Mayo (people) thyroid gland thyroiditis EMTREE MEDICAL INDEX TERMS adverse drug reaction autoimmune disease cancer patient differentiated thyroid cancer etiology female Hashimoto disease hormone substitution hypophysitis hypothyroidism male neoplasm pathophysiology patient patient care thyroid disease thyroid function thyroid function test LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72065616 DOI 10.1089/thy.2015.29004.abstracts FULL TEXT LINK http://dx.doi.org/10.1089/thy.2015.29004.abstracts COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 118 TITLE Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with recurrent or refractory ovarian cancer: A phase Ib trial reporting safety and clinical activity AUTHOR NAMES Disis M.L. Patel M. Pant S. Hamilton E.P. Lockhart A.C. Kelly K. Thaddeus-Beck J. Gordon M. Weiss G.J. Ejadi S. Taylor M.H. Chin K. Cuillerot J.M. Von Heydebreck A. Gulley J.L. AUTHOR ADDRESSES (Disis M.L.) University of Washington, School of Medicine, Pathology and Obstetrics and Gynecology, Seattle, United States. (Patel M.) Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, United States. (Pant S.) Peggy and Charles Stephenson Oklahoma Cancer Center, Hematoloty/Oncology, Oklahoma City, United States. (Hamilton E.P.) Sarah Cannon Research Institute, Tennessee Oncology, LLC, North Nashville, United States. (Lockhart A.C.) Washington University, Medical School, Hematology/Oncology, St. Louis, United States. (Kelly K.) UC Davis Comprehensive Cancer Center, Hematology/Oncology, Sacramento, United States. (Thaddeus-Beck J.) Highlands Oncology Group, Hematology/Oncology, Fayetteville, United States. (Gordon M.) Pinnacle Oncology Hematology, Hematology/Oncology, Scottsdale, United States. (Weiss G.J.) Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, United States. (Ejadi S.) Scottsdale Heatlhcare Research Institute, Hematology/Oncology, Scottsdale, United States. (Taylor M.H.) Knight Cancer Institute, Oregon Health and Science University, Portland, United States. (Chin K.) EMD Serono, Inc, Oncology Clinical Research, Billerica, United States. (Cuillerot J.M.) EMD Serono, Inc., Immuno-Oncology, Billerica, United States. (Von Heydebreck A.) Merck KGaA, R and D Global Biostatistics, Darmstadt, Germany. (Gulley J.L.) Genitourinary Malignancy Branch, National Cancer Institute, Center for Cancer Research, Bethesda, United States. CORRESPONDENCE ADDRESS M.L. Disis, University of Washington, School of Medicine, Pathology and Obstetrics and Gynecology, Seattle, United States. SOURCE European Journal of Cancer (2015) 51 SUPPL. 3 (S546-S547). Date of Publication: September 2015 CONFERENCE NAME European Cancer Congress 2015, ECC 2015 CONFERENCE LOCATION Vienna, Austria CONFERENCE DATE 2015-09-25 to 2015-09-29 ISSN 0959-8049 BOOK PUBLISHER Elsevier Ltd ABSTRACT Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab (MSB0010718C) is a fully human anti- PD-L1 IgG1 antibody being investigated in clinical trials. Here we report safety and clinical activity of avelumab in patients (pts) with previously treated, recurrent or refractory ovarian cancer (NCT01772004). Materials and Methods: Pts received avelumab at 10 mg/kg as a 1-h infusion Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumours were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response (BOR) and progression free survival (PFS) were evaluated and analyses of overall survival are ongoing. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Tumour PD-L1 expression at baseline was assessed by immunohistochemistry. Results: Seventy-five women with recurrent or refractory stage III-IV ovarian cancer were treated with avelumab. As of 13 Feb 2015, median duration of treatment was 12 wks (range, 2-54), and 8 pts remained on treatment. Median age was 62 y (range 38-84), ECOG performance status was 0 [41.3%] or 1 [58.7%], and pts had received a median of 5 lines of prior treatment (range, 2-≥5). Treatment-related treatment-emergent adverse events (TEAEs) of any grade occurred in 52 pts (69.3%); the most common (>10%) were fatigue (12 [16.0%]), chills (9 [12.0%]), nausea (8 [10.7%]), and diarrhoea (8 [10.7%]). There were 6 pts (8.0%) reporting treatment-related grade 3/4 TEAEs (none occurred in more than 1 pt) and no treatment-related grade 5 TEAEs. Objective responses were observed in 8 (10.7%) pts (95% CI: 4.7, 19.9). All were partial responses and 5 (62.5%) were ongoing at data cutoff. Tumour shrinkage by ≥30% in target lesions was observed in 3 additional pts (4.0%); however, these pts did not meet RECIST criteria for response. Stable disease was observed in 33 pts (44.0%). Median PFS was 11.4 wks (95% CI: 6.3, 12.0) and the PFS rate at 24 wks was 17.2% (95% CI: 8.1, 29.2). Tumours were PD-L1+ in 74.6% of evaluable pts (n = 67; 1% tumour expression cutoff). The ORR in PD-L1+ pts (n = 50) was 12.0% and 5.9% in PD-L1- pts (n = 17). OS data are immature at this time. Conclusions: Avelumab showed an acceptable safety profile and encouraging clinical activity in this largest-to-date cohort of pts with heavily pretreated, advanced ovarian cancer treated with anti-PD-(L)1 therapy. Analysis of PD-L1 expression shows a trend towards better response in PD-L1+ tumours. Additional clinical studies with avelumab as monotherapy and in combination with other agents in this pt population are planned. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody avelumab EMTREE DRUG INDEX TERMS ligand programmed death 1 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) European female human neoplasm ovary cancer patient safety EMTREE MEDICAL INDEX TERMS clinical study clinical trial (topic) diarrhea electrocorticography fatigue immune response immunohistochemistry infusion monotherapy nausea overall survival population progression free survival therapy toxicity treatment duration LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72068188 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 119 TITLE Thyroid cancer outcome and association with immune checkpoint proteins, programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1), lymphocytic infiltrates subsets and mutant B-Raf protein expression AUTHOR NAMES Han E.J. Sica G.L. Zhang C. Chen Z. Lawson D. Saba N.F. Shin D.M. Khuri F.R. Cohen C. Owonikoko T.K. AUTHOR ADDRESSES (Han E.J.; Sica G.L.; Zhang C.; Chen Z.; Lawson D.; Saba N.F.; Shin D.M.; Khuri F.R.; Cohen C.; Owonikoko T.K.) Emory University, Atlanta, United States. CORRESPONDENCE ADDRESS E.J. Han, Emory University, Atlanta, United States. SOURCE Thyroid (2015) 25 SUPPL. 1 (A137). Date of Publication: 2015 CONFERENCE NAME 15th International Thyroid Congress and 85th Annual Meeting of the American Thyroid Association CONFERENCE LOCATION Lake Buena Vista, FL, United States CONFERENCE DATE 2015-10-18 to 2015-10-23 ISSN 1050-7256 BOOK PUBLISHER Mary Ann Liebert Inc. ABSTRACT Thyroid cancer is the fastest growing endocrine cancer worldwide. Immune checkpoint therapy has emerged as a realistic therapeutic option in various cancers. We studied the expression of immune checkpoint proteins and association with prognostic biomarkers in thyroid cancer. We assessed protein expression by immunohistochemistry using antibodies targeting PD-1, PD-L1, mutant B-Raf, CD3 ( + ) and CD8 ( + ) lymphocytes in tissue microarray constructed from archival samples of resected thyroid cancer. Expression was quantified using standard algorithm of intensity (0, 1, 2 and 3), percent cell staining and H-score. Differences and correlation between protein expression and patient demographics (age, gender, race) tumor characteristics (stage, histology) and overall survival (OS), biochemical recurrence (BR) and anatomic recurrence (AR) were assessed by ANOVA and Log-rank test. We included samples from 223 patients; female 146 (72%), Asian (2.2%) Black (24%), Caucasian (68.9%) and Hispanic (2.7%); papillary cancer (61.3%), follicular carcinoma (12.2%) and anaplastic (5.4%). There were 100 cases (59.5%) in stage I, 19 (11.3%) stage II, 16.7% stage II and 12.5% in stage IV. The 5-year OS, BR-free survival and AR-free survival were: 96.5%, 95.5% and 94.6% respectively. There were significant differences in OS based on age [HR:0.17 (0.04-0.79) p = 0.010), stage [HR: 0.03 (0.01-0.12), p < .001] and iodine therapy [HR: 5.12 (1.48-17.72), p = 0.004]. Absence of node involvement was associated with reduced risk of AR [HR: 0.31 (0.09-1.00) p = 0.038] but not with BR [HR: 0.63 (0.15-2.65); p = 0.529]. PD-L1 expression was > 2 fold higher in tumors of deceased patients and of patients with distant metastasis. There was a higher expression of CD3 ( + ) lymphocytic infiltrate in patients with nodal disease and of mutant B-Raf protein expression in patients with recurrence and deceased patients. There was no significant difference in PD-1 expression or CD (8 + ) lymphocytic infiltrate across all categories of patients or tumor characteristics. PD-L1 and mutant B-Raf protein expression are associated with worse outcome in thyroid cancer patients. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) B Raf kinase ligand protein EMTREE DRUG INDEX TERMS antibody biological marker CD3 antigen CD8 antigen iodine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American apoptosis mutant protein expression thyroid cancer thyroid gland EMTREE MEDICAL INDEX TERMS algorithm analysis of variance Asian biochemical recurrence cancer patient Caucasian distant metastasis endocrine tumor female follicular carcinoma gender Hispanic histology human immunohistochemistry log rank test lymphocyte neoplasm overall survival patient risk staining survival therapy tissue microarray LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72065863 DOI 10.1089/thy.2015.29004.abstracts FULL TEXT LINK http://dx.doi.org/10.1089/thy.2015.29004.abstracts COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 120 TITLE Association of immune-related thyroid disorders with pembrolizumab (pembro, MK-3475) in patients (pts) with advanced melanoma treated in KEYNOTE-001 AUTHOR NAMES Robert C. Joshua A.M. Kefford R. Joseph R.W. Wolchok J.D. Hodi F.S. Hamid O. Weber J.S. Gangadhar T.C. Dronca R.S. Patnaik A. Zarour H.M. Hwu W.-J. Hersey P. Daud A. Giannotti M. Li X.N. Ebbinghaus S. Kang S.P. Ribas A. AUTHOR ADDRESSES (Robert C.; Joshua A.M.; Kefford R.; Joseph R.W.; Wolchok J.D.; Hodi F.S.; Hamid O.; Weber J.S.; Gangadhar T.C.; Dronca R.S.; Patnaik A.; Zarour H.M.; Hwu W.-J.; Hersey P.; Daud A.; Giannotti M.; Li X.N.; Ebbinghaus S.; Kang S.P.; Ribas A.) Gustave Roussy, Villejuif, France; Princess Margaret Cancer Centre, Toronto, ON, Canada; Macquarie University and Westmead Hospital, Sydney, Australia; Mayo Clinic, Jacksonville, FL; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; The Angeles Clinic and Research Institute, Los Angeles, CA; H. Lee Moffitt Cancer Center, Tampa, FL; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Mayo Clinic, Rochester, MN; START, San Antonio, TX; University of Pittsburgh, Pittsburgh, PA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Sydney, Sydney, Australia; UC San Francisco, San Francisco, CA; Merck & Co., Inc., Kenilworth, NJ; UCLA, Los Angeles, CA CORRESPONDENCE ADDRESS C. Robert, SOURCE Journal of Clinical Oncology (2015) 33:15 SUPPL. 1. Date of Publication: 20 May 2015 CONFERENCE NAME 2015 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2015-05-29 to 2015-06-02 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: The anti-PD-1 antibody pembro is approved in the US for treating advanced MEL that progressed following IPI and, if BRAFV600 mutant, a BRAF inhibitor. Immune- related AEs (irAEs) are of interest for immunotherapies such as pembro. Among the first 411 MEL pts treated with pembro in the phase 1 KEYNOTE-001 study (NCT01295827 ), 18% experienced irAEs (4% gr 3/4). We describe the incidence and treatment of thyroid disorders, the most common irAEs observed in KEYNOTE-001. Methods: AEs were monitored throughout treatment and for 30 d thereafter (serious AEs and potential irAEs for up to 90 d). AEs were graded per CTCAE v4.0. Thyroid disorders included hypothyroidism, hyperthyroidism, thyroiditis, and related terms. TSH and free T4 (FT4) levels were measured at baseline and once per treatment cycle. Results: Thyroid disorders occurred in 39 (9.5%) pts: hypothyroidism in 33 (8.0%), hyperthyroidism in 6 (1.5%), and thyroiditis in 3 (0.7%); 2 pts experienced both hypo- and hyperthyroidism, and 1 pt experienced hypothyroidism and thyroiditis. 2 events were of gr 3 severity: 1 hypo- and 1 hyperthyroidism. Hypothyroidism was managed with long-term hormone replacement therapy, with no permanent discontinuation required; only 4 pts required temporary pembro interruption. 2 pts with hyperthyroidism required corticosteroids, and 2 permanently discontinued pembro. Hyperthyroidism resolved in 83% of pts. Thyroiditis resolved in 67% of pts; no cases required treatment interruption, discontinuation, or corticosteroid use. Median time to onset and duration are shown in the Table. 111 (33.9%) pts had 1 abnormal postbaseline TSH or FT4 value, with subclinical hypo- and hyperthyroidism most common (20.5% and 19.3%, respectively). Conclusions: Thyroid disorders are the most frequent irAEs associated with pembro. Most events are of gr 1 or 2 severity and can be managed with supportive care and temporary treatment interruption. These findings support regular assessment of thyroid function in pembro recipients. (Table Presented ). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS antibody corticosteroid thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American human melanoma oncology patient society thyroid disease EMTREE MEDICAL INDEX TERMS hormone substitution hyperthyroidism hypothyroidism immunotherapy mutant recipient thyroid function thyroiditis LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72015087 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 121 TITLE Avelumab (MSB0010718C), an antiPDL1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, openlabel expansion trial AUTHOR NAMES Disis M.L. Patel M.R. Pant S. Infante J.R. Lockhart A..C. Kelly K. Beck J.T. Gordon M.S. Weiss G.J. Ejadi S. Taylor M.H. Von Heydebreck A. Chin K.M. Cuillerot J.-M. Gulley J.L. AUTHOR ADDRESSES (Disis M.L.; Patel M.R.; Pant S.; Infante J.R.; Lockhart A..C.; Kelly K.; Beck J.T.; Gordon M.S.; Weiss G.J.; Ejadi S.; Taylor M.H.; Von Heydebreck A.; Chin K.M.; Cuillerot J.-M.; Gulley J.L.) University of Washington School of Medicine, Seattle, WA; Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; Washington University School of Medicine, St. Louis, MO; UC Davis Comprehensive Cancer Center, Sacramento, CA; Highlands Oncology Group, Rogers, AR; Pinnacle Oncology Hematology, Scottsdale, AZ; Western Regional Medical Center, Cancer Treatment Centers of America, Goodyear, AZ; Virginia G. Piper Cancer Center, Scottsdale, AZ; Oregon Health and Science University, Portland, OR; Merck KGaA, Darmstadt, Germany; EMD Serono, Billerica, MA; National Cancer Institute, National Institutes of Health, Bethesda, MD CORRESPONDENCE ADDRESS M.L. Disis, SOURCE Journal of Clinical Oncology (2015) 33:15 SUPPL. 1. Date of Publication: 20 May 2015 CONFERENCE NAME 2015 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2015-05-29 to 2015-06-02 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: The programmed death1 receptor (PD1) and its ligand (PDL1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab (proposed INN) (MSB0010718C) is a fully human antiPDL1 IgG1 antibody currently being investigated in clinical trials. Here we present results from a cohort of patients (pts) with recurrent or refractory ovarian cancer in an ongoing phase Ib study (NCT01772004 ). Methods: Pts with ECOG PS 01 received avelumab at 10 mg/kg Q2W. Best overall response (BOR) and progressionfree survival (PFS) were assessed according to RECIST 1.1. Adverse events (AEs) were evaluated by CTCAE v4.0. A prespecified analysis of 23 pts with followup of 2 months showed confirmed and unconfirmed partial responses (PRs), leading to cohort expansion to 75 pts. Results: Seventyfive pts were enrolled from November 2013 to November 2014 (median age 62 [range 3884] ; ECOG PS 0 [41%] or 1 [59%]; median of four prior lines of therapy). As of January 2015, median duration of treatment with avelumab was 10 weeks (range 254 weeks), and 27 pts remained on treatment. Efficacy data from the 23 pts followedup for 2 months (range 2- 8 months) demonstrated 4 pts (17.4%, [95% CI, 5.0%, 38.8%]) achieved an unconfirmed BOR of PR,11 (47.8%) had stable disease, and 2 pts had >30% tumor shrinkage after progression was reported. Median PFS was 11.9 weeks (95% CI, 5.9, not reached), and the PFS rate at 24 weeks was 33.3% (95% CI, 11.5, 57.2). Drugrelated treatmentemergent AEs (TEAEs; all grades) were reported in 18 pts (78.3%), and 2 pts (8.7%) experienced grade 3 drugrelated TEAEs (increased lipase [1] and elevated creatine kinase and autoimmune myositis that led to discontinuation [1]). No drugrelated serious TEAEs occurred. The most commonly reported drugrelated TEAEs (> 10%) were fatigue, nausea, and diarrhea. Conclusions: These data represent the largest reported dataset of pts with recurrent ovarian cancer treated with antiPDL1 therapy. Avelumab demonstrated an acceptable safety profile and is clinically active in this heavily pretreated ovarian cancer pt population. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody avelumab EMTREE DRUG INDEX TERMS creatine kinase ligand receptor triacylglycerol lipase EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American female human oncology ovary cancer patient society EMTREE MEDICAL INDEX TERMS clinical trial (topic) diarrhea electrocorticography fatigue follow up immune response multiple cancer myositis nausea neoplasm population safety survival therapy treatment duration LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72015388 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 122 TITLE Antitumor activity and safety of pembrolizumab in patients (pts) with PDL1 positive advanced ovarian cancer: Interim results from a phase Ib study AUTHOR NAMES Varga A. Piha-Paul S.A. Ott P.A. Mehnert J.M. Berton-Rigaud D. Johnson E.A. Cheng J.D. Yuan S. Rubin E.H. Matei D.E. AUTHOR ADDRESSES (Varga A.; Piha-Paul S.A.; Ott P.A.; Mehnert J.M.; Berton-Rigaud D.; Johnson E.A.; Cheng J.D.; Yuan S.; Rubin E.H.; Matei D.E.) Gustave Roussy Institute, Villejuif, France; The University of Texas MD Anderson Cancer Center, Houston, TX; DanaFarber Cancer Institute, Boston, MA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; ICO Centre René Gauducheau, SaintHerblain, France; Merck and Co., Inc., Kenilworth, NJ; Indiana University, Indianapolis, IN CORRESPONDENCE ADDRESS A. Varga, SOURCE Journal of Clinical Oncology (2015) 33:15 SUPPL. 1. Date of Publication: 20 May 2015 CONFERENCE NAME 2015 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2015-05-29 to 2015-06-02 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Pembrolizumab is a potent, highly selective humanized monoclonal antibody against PD1 designed to block interaction with PDL1 and PDL2 and remove the inhibition of Tcell activation against cancer. PDL1 was found to be overexpressed in ovarian cancer and can contribute to malignancy. We assessed the safety and efficacy of pembrolizumab in pts with PDL1+ advanced ovarian cancer. Methods: KEYNOTE028 (NCT02054806 ) is a nonrandomized, multicohort phase Ib trial of pembrolizumab in pts with PDL1+ advanced solid tumors. Key eligibility criteria for the ovarian cancer cohort included advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of prior therapy; PDL1 expression in 1% of cells in tumor nests or PDL1+ bands in stroma as determined by a prototype IHC assay at a central laboratory; and ECOG PS 01. Pembrolizumab 10 mg/kg was given every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points: safety, tolerability, and preliminary efficacy. Response assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Results: 26 pts were enrolled. Mean (SD) age was 58.1 (7.5); 57.7% were white. 84.6% received prior therapies for recurrent/metastatic disease (38.5% received 5 therapies), and 50% received prior adjuvant therapies. One pt achieved complete response and 2 pts experienced partial response; 6 pts had stable disease. Of the 3 patients who responded, all remain in response with duration of response 24 weeks at the time of analysis. The best overall (confirmed) response was 11.5% (95% CI, 2.430.2). 6/26 (23.1%) had evidence of tumor reduction; 3 had a tumor reduction of at least 30%. All pts experienced 1 adverse event (AE) (regardless of treatment); most common were fatigue (42.3%), anemia (30.8%), and decreased appetite (30.8%). Drugrelated AEs occurred in 69.2% of pts (grade 3, 1/26 pts). Currently, 6 pts remain on pembrolizumab treatment. Conclusions: PD1 blockade with pembrolizumab is well tolerated and has antitumor activity in pts with advanced ovarian cancer. This preliminary signal for clinical efficacy will be further investigated. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) pembrolizumab EMTREE DRUG INDEX TERMS monoclonal antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American antineoplastic activity female human oncology ovary cancer patient safety society EMTREE MEDICAL INDEX TERMS adjuvant therapy anemia assay carcinoma decreased appetite electrocorticography Fallopian tube fatigue laboratory neoplasm solid malignant neoplasm stroma therapy toxicity LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72015310 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 123 TITLE Durable tumor remission in patients with platinumresistant ovarian cancer receiving nivolumab AUTHOR NAMES Hamanishi J. Mandai M. Ikeda T. Minami M. Kawaguchi A. Matsumura N. Abiko K. Baba T. Yamaguchi K. Ueda A. Hosoe Y. Morita S. Shimizu A. Honjo T. Konishi I. AUTHOR ADDRESSES (Hamanishi J.; Mandai M.; Ikeda T.; Minami M.; Kawaguchi A.; Matsumura N.; Abiko K.; Baba T.; Yamaguchi K.; Ueda A.; Hosoe Y.; Morita S.; Shimizu A.; Honjo T.; Konishi I.) Kyoto University, Kyoto, Japan; Kinki University, Osaka, Japan; Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan CORRESPONDENCE ADDRESS J. Hamanishi, SOURCE Journal of Clinical Oncology (2015) 33:15 SUPPL. 1. Date of Publication: 20 May 2015 CONFERENCE NAME 2015 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2015-05-29 to 2015-06-02 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Programmed death1 (PD1) is a coinhibitory receptor expressed on activated T cells which regulates antitumor immunity. Nivolumab is a fullyhumanized IgG4 that blocks the engagement of PD1 by PD1 ligands. We previously showed nivolumab can mediate tumor regression in a substantial proportion of patients with ovarian cancer in phase II trial (ASCO 2014, UMIN000005714), but the potential of durable antitumor response by nivolumab for these patients was unknown. Methods: Patients with platinumresistant ovarian cancer (n=20) enrolled from 2011 to 2014 were treated with nivolumab (1mg/kg, n=10; 3mg/kg, n=10, each) intravenously every two weeks up to one year were followed how long antitumor response continued. Results: Among 20 patients in whom response could be evaluated, we followed two patients with complete response in 3mg/kg cohort and one patient with partial response of 1mg/kg cohort. At the time of data cut off, a partial responder had responses for 5 months, and two complete responders survived without disease progression for 17 and 14 months, each. The duration of response of these patients after treatment discontinuation was 6months and 3months, each. Conclusions: Antitumor responses were durable and continued after niolumabtreatment discontinuation. Now we explore the biomarker of these responders and next phase of clinical trials will further assess the significance of nivolumab on survival in patients with ovarian cancer. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) nivolumab EMTREE DRUG INDEX TERMS biological marker ligand receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) American female human oncology ovary cancer patient society tumor regression EMTREE MEDICAL INDEX TERMS clinical trial (topic) disease course immunity phase 2 clinical trial survival T lymphocyte LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L72015423 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 124 TITLE Durable anti-tumor response of nivolumab (anti-PD-1 antibody) for platinum-resistant ovarian cancer; phase II clinical trial with nivolumab AUTHOR NAMES Hamanishi J. Mandai M. Matsumura N. Abiko K. Baba T. Yamaguchi K. Konishi I. AUTHOR ADDRESSES (Hamanishi J.; Matsumura N.; Abiko K.; Baba T.; Yamaguchi K.; Konishi I.) Kyoto University, Kyoto, Japan. (Mandai M.) Kinki University, Osakasayama, Japan. CORRESPONDENCE ADDRESS J. Hamanishi, Kyoto University, Kyoto, Japan. SOURCE Gynecologic Oncology (2015) 137 SUPPL. 1 (23). Date of Publication: April 2015 CONFERENCE NAME 46th Annual Meeting on Women's Cancer of the Society of Gynecologic Oncology, SGO 2015 CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2015-03-28 to 2015-03-31 ISSN 0090-8258 BOOK PUBLISHER Academic Press Inc. ABSTRACT Objectives: Programmed death-1 (PD-1) is a coinhibitory receptor expressed on activated T cells that relates to regulation of antitumor immunity. Nivolumab is a fully human immunoglobulin G4 that blocks the binding of PD-1 and PD-1 ligand (PD-L1). In this report, we present antitumor activity and durable tumor remission cases achieved with nivolumab in ovarian cancer patients. Methods: Nivolumab was administered every 2 weeks to patients with advanced or relapsed platinum-resistant ovarian cancer at the doses of 1 or 3 mg/kg during two cohort examinations with 10 patients in each cohort. The phase II trial defined the primary endpoint of response rate, and secondary endpoints of safety and rate of disease control. Patients received up to 6 cycles (4 doses/cycle) of nivolumab treatment for 1 year or until PD or disease progression. Response rate was assessed by Response Evaluation Criteria in Solid Tumors v1.1, and adverse events were evaluated by Common Terminology Criteria for Adverse Events v4.0. The data were cut off on May 31, 2014. Results: Twenty patients were treated with nivolumab (1 mg/kg: n=10; 3 mg/kg: n=10) and evaluated. Median duration of therapy was 14 weeks. One patient had a severe adverse drug reaction with fever, disorientation, and gait disturbance. Among 20 patients in whom response could be evaluated, the best response rate of the 3-mg/kg cohort was 20% (2 patients with complete response); the best response rate of the 1-mg/kg cohort was 10% (1 patient with partial response). The disease control rate for the 3-mg/kg cohort was 40% (2 patients with stable disease [SD]) and for the 1-mg/kg cohort was 50% (4 patients with SD). At the time of data cut-off, 1 partial responder had a response for 5 months and 2 complete responders were on study with response for 9 and 6 months each. Conclusions: Nivolumab administered at 1 mg/kg is well tolerated and has encouraging clinical efficacy for advanced or relapsed platinum resistant ovarian cancer. The 3-mg/kg dose may be more favorable than 1-mg/kg one, and the patient cohort receiving this dose is now under investigation. Nivolumab showed durable antitumor remission with complete response cases of ovarian cancers (WHO International Clinical Trials Registry Platform: JPRN-UMIN000005714). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody nivolumab platinum EMTREE DRUG INDEX TERMS human immunoglobulin ligand receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female human neoplasm oncology ovary cancer phase 2 clinical trial society EMTREE MEDICAL INDEX TERMS adverse drug reaction antineoplastic activity cancer patient cancer staging clinical trial (topic) death disease control disease course disorientation examination fever gait immunity patient register remission safety T lymphocyte treatment duration tumor regression LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71869464 DOI 10.1016/j.ygyno.2015.01.054 FULL TEXT LINK http://dx.doi.org/10.1016/j.ygyno.2015.01.054 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 125 TITLE Immunotherapy related neurological complications ipilimumab induced hypophysitis pachymeningitis and other immune related neurological complications AUTHOR NAMES Gadde J. Iaia A. AUTHOR ADDRESSES (Gadde J.; Iaia A.) Christiana Care Health System Diagnostic Radiology, Newark, United States. CORRESPONDENCE ADDRESS J. Gadde, Christiana Care Health System Diagnostic Radiology, Newark, United States. SOURCE Neuroradiology (2014) 56 SUPPL. 1 (325-326). Date of Publication: September 2014 CONFERENCE NAME 20th Symposium Neuroradiologicum 2014 CONFERENCE LOCATION Istanbul, Turkey CONFERENCE DATE 2014-09-07 to 2014-09-12 ISSN 0028-3940 BOOK PUBLISHER Springer Verlag ABSTRACT PURPOSE: 1. To review the human monoclonal antibody ipilimumab, its mechanism of action and its clinical use in patients with metastatic melanoma. 2. To review rare immune-related neurological complications associated with the use of ipilimumab, discuss their clinical presentation, treatment and patient prognosis. 3. To illustrate the MR imaging features of immune-related neurological complications of ipilimumab, with emphasis on hypophysitis and pachymeningitis. METHODS: Gadolinium enhanced MRI of the sella turcica was performed at our institution in patients prior to initiation of ipilimumab therapy, at the time of development of hypophysitis and pachymeningitis and following discontinuation of ipilimumab therapy. The majority of the illustrations are from two patients with documented ipilimumab-induced hypophysitis, one of which also demonstrated associated pachymeningitis. Additional images included in the poster are of three cases seen at a different institution. RESULTS: MR imaging findings of hypophysitis and pachymeningitis secondary to ipilimumab therapy are illustrated, with description of the patients' clinical symptoms and review of their endocrinologic data confirming hypophysitis. A remarkable increase in size of the hypophysis is observed following two doses of ipilimumab. Upon cessation of therapy, the hypophysis decreases rapidly in size. Remarkable atrophy in our patients' hypophysis correlates with clinical evidence of hypopituitarism requiring hormone replacement therapy. Pachymeningeal thickening and enhancement in one patient resolved completely after cessation of ipilimumab therapy. Additional neurological complications associated with ipilimumab are illustrated, with images and clinical vignettes documenting these entities. CONCLUSIONS: Ipilimumab is a human monoclonal antibody used for treatment of metastatic melanoma. It inhibits the suppressive effects of cytotoxic T-lymphocyte antigen 4 expression and potentiates the body's immune response against tumors. This immunosuppression can lead to several autoimmune disorders. Neurological complications include autoimmune hyophysitis and pachymeningitis, disorders that are reversible with cessation of ipilimumab therapy. Neuroradiologists should be familiar with the MR imaging appearance of these complications as recognition can lead to prompt treatment and better patient outcome. (Figure Presented). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 gadolinium human monoclonal antibody EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis immunotherapy neurological complication EMTREE MEDICAL INDEX TERMS atrophy autoimmune disease diseases hormone substitution human hypophysis hypopituitarism immune response immunosuppressive treatment metastatic melanoma neoplasm neuroradiologist nuclear magnetic resonance imaging patient prognosis sella turcica therapy vignette LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71812846 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 126 TITLE Ipilimumab-induced hypophysitis and thyroiditis AUTHOR NAMES Thompson B.M. Joshi R. AUTHOR ADDRESSES (Thompson B.M.) Washington Univ, St. Louis, United States. (Joshi R.) Washington University, St. Louis, United States. CORRESPONDENCE ADDRESS B.M. Thompson, Washington Univ, St. Louis, United States. SOURCE Endocrine Reviews (2013) 34:3 SUPPL. 1. Date of Publication: 2013 CONFERENCE NAME 95th Annual Meeting and Expo of the Endocrine Society, ENDO 2013 CONFERENCE LOCATION San Francisco, CA, United States CONFERENCE DATE 2013-06-15 to 2013-06-18 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Ipilimumab, a monoclonal antibody against the cytotoxic T lymphocyte 4 antigen (CTLA-4), is currently approved for the treatment of unresectable and advanced metastatic melanoma. Immune related adverse events (IRAEs) are a common side effect of treatment. The development of IRAEs is associated with a better drug response. Of the different types of IRAEs, endocrinopathies account for 7%. The decision to discontinue ipilimumab in patients who develop IRAEs is currently debated. We present a case of combined hypophysitis and thyroiditis in a patient receiving ipilimumab. Although individually both are well-described presentations, there are no cases in the literature describing this combination. Clinical Case: A 52 year old man with metastatic melanoma presented with progressive fatigue, headache, anorexia, and nausea. He had received his third dose of ipilimumab three weeks prior to the onset of symptoms. On examination, he was afebrile, normotensive, and tachycardic. Neurological exam revealed normal extraocular movements and intact visual fields. No evidence of goiter or thyroid tenderness was noted. Abdomen was soft without organomegaly and no lymphadenopathy was appreciated. Laboratory evaluation revealed a TSH of <0.02 mcIU/ml (n = 0.35- 5.5) and free T4 of 2.29 ng/dl (n= 0.9- 1.8). Thyroid stimulating Ig and thyroperoxidase Ab were negative. Prolactin was low at 1.7 ng/mL (n= 2.1-18.0). Morning cortisol was undetectable at <1.5 mcg/dL. 21-hydroxylase Ab was negative. He had low gonadotropins with LH of 1.3 IU/L (n= 1.5-9.3) and FSH of 1.7 IU/L (1.4-18.0) with a total testosterone level of <50 ng/dL (n= 24-827). Brain MRI was negative for metastases. A diagnosis of combined autoimmune hypophysitis and thyroiditis was made. The ipilimumab was continued and the endocrinopathies treated medically. Stress dose steroids resulted in immediate resolution of his symptoms. Methimazole resulted in euthyroidism. Testosterone was withheld given a concern for tumor growth. He demonstrated decreased tumor size on follow-up imaging. The thyroiditis resolved following the completion of ipilimumab treatment. He has required long term maintenance steroids. Conclusion: An increasing number of patients will receive anti-CTLA-4 therapies for metastatic melanoma. Endocrinologists should be aware of the potential endocrine derangements that may occur, screening recommendations, and the treatment considerations associated with these endocrinopathies. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS antigen cytotoxic T lymphocyte antigen 4 follitropin gonadotropin hydrocortisone immunoglobulin monoclonal antibody prolactin steroid steroid 21 monooxygenase testosterone thiamazole thyroid peroxidase thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis society thyroiditis EMTREE MEDICAL INDEX TERMS abdomen anorexia brain cytotoxic T lymphocyte diagnosis drug response endocrinologist euthyroidism examination fatigue follow up goiter headache human imaging laboratory lymphadenopathy male metastasis metastatic melanoma nausea nuclear magnetic resonance imaging patient screening side effect therapy thyroid gland tumor growth tumor volume visual field LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71783894 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 127 TITLE Autoimmune hypophysitis due to ipilimumab AUTHOR NAMES Gil S.M. Aparicio M. Bertini K. Rodriguez F. Sankowicz S. Ballarino C. AUTHOR ADDRESSES (Gil S.M.; Aparicio M.; Bertini K.; Rodriguez F.; Sankowicz S.; Ballarino C.) Hospital Militar Central, Buenos Aires, Argentina. CORRESPONDENCE ADDRESS S.M. Gil, Hospital Militar Central, Buenos Aires, Argentina. SOURCE Endocrine Reviews (2013) 34:3 SUPPL. 1. Date of Publication: 2013 CONFERENCE NAME 95th Annual Meeting and Expo of the Endocrine Society, ENDO 2013 CONFERENCE LOCATION San Francisco, CA, United States CONFERENCE DATE 2013-06-15 to 2013-06-18 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Ipilimumab is an immunostimulatory drug used in cancers and may induce immune adverse effects, such as hypophysitis. Clinical case: an 80-year-old man was admitted to the hospital because he presented a 3-week history of flue-like syndrome, abdominal pain, arterial hypotension and neurological decline with lethargy, tiredness, loss of appetite, constipation following the second course of ipilimumab for recurrent prostate cancer with multiple bone metastases. He had been previously treated with GNRH analogs and chemotherapy without response. At physical examination he presented: arterial hypotension, sleepiness, pale and dry skin and mucouses, lethargy, dysphonia, edema in lower limbs and abdominal distension. In laboratory studies he presented anemia, hyponatraemia, slight hyperglycemia (he had type 2 diabetes) and mild increase of urea and creatinine. The patient was treated with: fluid reposition, blood transfusion and 5 consecutives courses of 1,000 mg/day of methyl-prednisolone. The patient improved symptoms, anemia and renal function. Hormonal levels: TSH: 0.09 uU/ml (NV: 0.27-4.7) , T4: 3.63 ug/dl (4.5-12) , FSH: 1 mUI/ml (1.5-12.4) , LH: <0.1 mUI/ml (2-9), Testosterone: 0.29 ng/ml (1.32-8.92), Prolactin: 9 ng/ml (4.6-21.4), IGF-1: 31.5 ng/ml (94-267). He was started on hydrocortisone: 200 mg/day and levothyroxine 100 ug/day and triiodothyronine: 20 ug/d. Pituitary MRI was normal. Seven days later, FT4 was normal, we stopped triiodothyronine. On the 10° day of hospitalization, he presented diarrhea which did not stop despite being treated with bismuth and loperamide. He was restarted on courses of methyl- prednisolone with 1g/day of mesalazine with poor response. On the 15° day, he presented maculopapular rash on face, chest, back and upper limbs. On the 17° day, the patient presented neurological and clinical deterioration, significant increase of transaminases. Finally, the patient died. Conclusions: Our patient presented most of the ipilimumab immune adverse effects: anterior panhypopituitarism, colitis, dermatitis and hepatitis. Ipilimumab-induced hypophysitis is a new event that we need to address because this drug is a new cause of this rare pathology. We need to be rapidly aware of ipilimumab-induced hypophysitis in order to make an early diagnosis of this endocrinopathy; however, the prognosis of the patients depends on the presence of other immune adverse effects and on the cancer type. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS aminotransferase bismuth creatinine follitropin hydrocortisone levothyroxine liothyronine loperamide mesalazine methylprednisolone prolactin testosterone thyrotropin urea EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis society EMTREE MEDICAL INDEX TERMS abdominal distension abdominal pain adverse drug reaction anemia arm blood transfusion bone metastasis chemotherapy colitis constipation dermatitis deterioration diarrhea dry skin dysphonia early diagnosis edema endocrine disease fatigue hepatitis hospital hospitalization human hyperglycemia hyponatremia hypophysis hypopituitarism hypotension kidney function laboratory leg lethargy liquid loss of appetite maculopapular rash male neoplasm non insulin dependent diabetes mellitus nuclear magnetic resonance imaging pathology patient physical examination prognosis prostate cancer somnolence thorax LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71784942 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 128 TITLE Adrenal crisis secondary to hypophysitis after ipilimumab therapy and steroid treatment AUTHOR NAMES Sarvaideo J.L. Block R.J. Brockstein B. Meyer J. AUTHOR ADDRESSES (Sarvaideo J.L.) NorthShore University Health System, Evanston, United States. (Block R.J.) Northshore University Healthsystem, Highland Park, United States. (Brockstein B.; Meyer J.) NorthShore University HealthSystems, Evanston, United States. CORRESPONDENCE ADDRESS J.L. Sarvaideo, NorthShore University Health System, Evanston, United States. SOURCE Endocrine Reviews (2013) 34:3 SUPPL. 1. Date of Publication: 2013 CONFERENCE NAME 95th Annual Meeting and Expo of the Endocrine Society, ENDO 2013 CONFERENCE LOCATION San Francisco, CA, United States CONFERENCE DATE 2013-06-15 to 2013-06-18 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Hypophysitis is a known side effect of ipilimumab, an antibody that binds to CTLA-4 preventing the deactivation of T cells. Ipilimumab has been shown to improve median and long-term survival in metastatic melanoma, which is a major advancement for patients. Case: A 63 year-old female nurse with hypothyroidism was diagnosed with metastatic melanoma and treated with ipilimumab. After 4 cycles, her oncologist referred her to endocrinology for central hypothyroidism. She complained of longstanding intermittent headaches at that time with some baseline fatigue. She had no symptoms of nausea, vomiting, abdominal pain or orthostasis. She was instructed on the symptoms of adrenal insufficiency, since it is a side effect of ipilimumab, and labs were ordered. Five days later, before she had her labs drawn, she presented to the ED with severe headaches, weakness, dizziness and nausea. MRI revealed enlargement of the pituitary gland (gland height = 11.7 mm). Labs revealed an ACTH <5 pg/mL (normal 20-100), TSH .074 U/mL (normal 0.4-4.5), cortisol 0.4 ug/dL (normal 5-23), FSH 11.8 mU/mL (normal 40-250) and LH 2.1 mU/mL (normal 30-200). Patient was given methylprednisone 100 mg IV once and hydrocortisone 50 mg IV every 8 hours until her symptoms resolved. She was discharged on prednisone 60mg/day and tapered to hydrocortisone 20/10 mg daily. MRI was repeated 3 weeks later showing a decrease in the size of the pituitary gland, but still larger than baseline. MRI was repeated again 6 months later showing similar morphology to her baseline MRI prior to ipilimumab therapy. The plan was to continue to attempt a steroid taper but she decided to enroll in hospice care. Conclusion: If adrenal insufficiency is suspected in patients taking ipilimumab and low ACTH/cortisol levels are found, initiation of corticosteroids should be immediately administered to the patient. Pituitary MRI can confirm the diagnosis. Rapid response is often seen. The goal is to taper the steroids but many patients require long-term therapy. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab steroid EMTREE DRUG INDEX TERMS antibody corticosteroid corticotropin cytotoxic T lymphocyte antigen 4 follitropin hydrocortisone meprednisone prednisone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal cortex insufficiency hypophysitis society therapy EMTREE MEDICAL INDEX TERMS abdominal pain adrenal insufficiency diagnosis dizziness endocrinology fatigue female headache height hospice care human hypophysis hypothyroidism long term care long term survival metastatic melanoma morphology nausea nuclear magnetic resonance imaging nurse oncologist patient side effect standing T lymphocyte vomiting weakness LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71784944 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 129 TITLE Central adrenal insufficiency due to ipilimumab (Yervoy) AUTHOR NAMES Ahmed M.K. Rein V. Shenker Y. Albertini M. Davis D.B. AUTHOR ADDRESSES (Ahmed M.K.; Rein V.; Shenker Y.; Albertini M.; Davis D.B.) University of Wisconsin, Madison, United States. CORRESPONDENCE ADDRESS M.K. Ahmed, University of Wisconsin, Madison, United States. SOURCE Endocrine Reviews (2013) 34:3 SUPPL. 1. Date of Publication: 2013 CONFERENCE NAME 95th Annual Meeting and Expo of the Endocrine Society, ENDO 2013 CONFERENCE LOCATION San Francisco, CA, United States CONFERENCE DATE 2013-06-15 to 2013-06-18 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Background: Ipilimumab (IPI) is a monoclonal Ab that blocks cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). In patients with metastatic melanoma (MM), IPI increases survival time and induces complete remission in some patients (1). By blocking CTLA-4 with IPI, the antitumor activity of melanoma reactive T cells can be up regulated. Immune-related adverse effects (irAEs) were noted in clinical trials. The most commonly reported endocrine dysfunction is hypophysitis, occurring in 4-6% of patients after 9 weeks of therapy. Unlike most of the other irAEs, endocrine dysfunction caused by IPI appears to have a protracted course and in many cases requires lifelong therapy (2). We are reporting 3 patients who presented with symptomatic central adrenal insufficiency after being treated with IPI. Clinical Case 1: A 60 year old female was diagnosed with MM in July 2011. 4 cycles of IPI were given, ending in March 2012. In July 2012 she developed severe hyponatremia and was diagnosed with central adrenal insufficiency. Remainder of pituitary labs and MRI of head were unremarkable. She was started on hydrocortisone replacement therapy. Her most recent melanoma evaluation in Sep 2012 had evidence of delayed response in her lung nodules. Repeat testing showed persistent adrenal insufficiency. 2. A 71 year old male was diagnosed with melanoma recurrence in May 2012. 4 cycles of IPI were given, ending in July 2012. Two weeks after getting IPI he developed proximal muscle weakness and fatigue. MRI of the head showed hypophysitis. Pituitary labs showed hypopituitarism with thyroid, gonadotropin and ACTH abnormalities. His most recent evaluation in Dec 2012 had almost complete resolution of disease. He remains on hydrocortisone, thyroid and testosterone replacement therapy. 3. A 74 year old male was diagnosed with MM in Dec 2011. 4 cycles of IPI were given , ending in April 2012. Shortly after, he developed headaches and fatigue. MRI of the head showed hypophysitis. Pituitary labs showed hypopituitarism with thyroid, gonadotropin and ACTH abnormalities. He is on hydrocortisone, thyroid and testosterone replacement therapy. Currently he is being treated with temozolomide. Conclusion: The enhanced immunity with IPI appears to frequently target the anterior pituitary gland. Evaluation of pituitary gland function should be considered with IPI therapy. It is unknown if IPI induced hypophysitis is reversible. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticotropin cytotoxic T lymphocyte antigen 4 gonadotropin hydrocortisone temozolomide EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency society EMTREE MEDICAL INDEX TERMS adenohypophysis adverse drug reaction androgen therapy antineoplastic activity clinical trial (topic) endocrine disease fatigue female headache human hyponatremia hypophysis hypophysitis hypopituitarism immunity lung nodule male melanoma metastatic melanoma muscle weakness nuclear magnetic resonance imaging patient remission substitution therapy survival time T lymphocyte therapy thyroid gland LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71784946 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 130 TITLE Immunreactivity for CTLA-4 in adenohypophysis and neutrophils suggest antibody dependent cytotoxicity to trigger ipilimumab induced hypophysitis AUTHOR NAMES Bjasch D. Maggio E.M. Fitsche A. Goldinger S.M. Moch H. Dummer R. Mihic-Probst D.C. AUTHOR ADDRESSES (Bjasch D.; Maggio E.M.; Fitsche A.; Moch H.; Mihic-Probst D.C.) Surgical Pathology, University Hospital Zürich, Zürich, Switzerland. (Bjasch D.) Surgical Pathology, Cantonal Hospital, St. Gallen, Switzerland. (Goldinger S.M.; Dummer R.) Dermatology, Universitiy Hospital Zürich, Zürich, Switzerland. CORRESPONDENCE ADDRESS D. Bjasch, Surgical Pathology, University Hospital Zürich, Zürich, Switzerland. SOURCE Pigment Cell and Melanoma Research (2014) 27:6 (1176). Date of Publication: November 2014 CONFERENCE NAME Society for Melanoma Research 2014 Congress CONFERENCE LOCATION Zurich, Switzerland CONFERENCE DATE 2014-11-13 to 2014-11-16 ISSN 1755-1471 BOOK PUBLISHER Blackwell Publishing Ltd ABSTRACT CTLA-4 is considered as a checkpoint inhibitory receptor during T cell activation. Ipilimumab, blocks CTLA-4 dependent T cell inhibition. Hypophysitis is frequent adverse reaction, which is postulated to be immune related. We show the morphologic correlate in a patient treated with ipilimumab for metastatic melanoma with clinical and laboratory signs of hypophysitis. The autopsy identifies numerous spotty necroses with granulocytic reaction in the anterior pituitary gland. There was no lympho-histiocytic infiltration. Instead we found strong positivity for CTLA-4, especially in the acidophil cells of the anterior pituitary gland. The neurohypophysis was negative for CTLA-4. In addition, the autopsy showed much more tumor progression than clinically suspected with multiple mets to the heart. Autopsy analyses of nine normal pituitary glands of patients with no history of hypophysitis confirmed our finding with exclusive positivity for CD3 and CTLA-4 in the adenohypophysis Our finding with positivity for CTLA-4 in eosinophil anterior pituitary gland cells, the numerous spotty necroses with granulocytic reaction, and the absence of lympho-histiocytic infiltration suggests an antibody-dependent cytotoxicity as a possible mechanism for ipilimumab related hypophysitis. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody cytotoxic T lymphocyte antigen 4 ipilimumab EMTREE DRUG INDEX TERMS CD3 antigen receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adenohypophysis cytotoxicity hypophysitis melanoma neutrophil society EMTREE MEDICAL INDEX TERMS adverse drug reaction autopsy eosinophil heart human hypophysis hypophysis cell laboratory metastatic melanoma necrosis neurohypophysis patient T lymphocyte T lymphocyte activation tumor growth LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71772254 DOI 10.1111/pcmr.12317 FULL TEXT LINK http://dx.doi.org/10.1111/pcmr.12317 COPYRIGHT Copyright 2015 Elsevier B.V., All rights reserved. RECORD 131 TITLE A phase ii clinical trial of immunotherapy with anti-PD-1 antibody (nivolumab) in advanced / relapsed, platinum-resistant ovarian cancer AUTHOR NAMES Hamanishi J. Mandai M. Matsumura N. Abiko K. Baba T. Yamaguchi K. Ueda M. Horikawa N. Murakami R. Koshiyama M. Konishi I. AUTHOR ADDRESSES (Hamanishi J.; Matsumura N.; Abiko K.; Baba T.; Yamaguchi K.; Ueda M.; Horikawa N.; Murakami R.; Koshiyama M.; Konishi I.) Gynecology and Obstetrics, Kyoto University, Graduate School of Medicine, Kyoto, Japan. (Mandai M.) Obstetrics and Gynecology, Kinki University, Graduate School of Medicine, Kyoto, Japan. CORRESPONDENCE ADDRESS J. Hamanishi, Gynecology and Obstetrics, Kyoto University, Graduate School of Medicine, Kyoto, Japan. SOURCE International Journal of Gynecological Cancer (2014) 24:9 SUPPL. 4 (400-401). Date of Publication: May 2014 CONFERENCE NAME 15th Biennial Meeting of the International Gynecologic Cancer Society CONFERENCE LOCATION Melbourne, VIC, Australia CONFERENCE DATE 2014-11-08 to 2014-11-11 ISSN 1048-891X BOOK PUBLISHER Lippincott Williams and Wilkins ABSTRACT Aims Programmed death-1 (PD-1) is a co-inhibitory receptor expressed on activated T cells and relates to regulate anti-tumor immunity. Nivolumab is a fully human IgG4 that blocks the binding of PD-1 and PD-1 ligand (PDL1). In this report we present anti-tumor activity with Nivolumab in ovarian cancer patients. Methods Nivolumab was administered every 2 weeks to patients with advanced or relapsed, platinum-resistant ovarian cancer, at the doses of 1 or 3 mg/kg during two cohort examination in each 10 patients. The phase II trial defined 1st endpoint of response rate, and 2nd endpoints of safety, and disease control rate. Patients received Nivolumab up to one year of treatment or until PD or disease progression. Response rate was assessed by RECIST, and adverse events were evaluated by CTCAE. The data were cut-off on 31 March, 2014. Results Eighteen patients were treated with nivolumab (1 mg/kg: n=10, 3mg/kg: n=8), and evaluated. There was two patient who had severe adverse drug reaction. One patient had events of fever, disorientation and gait disturbance. Another had severe fever elevation. Clinical response rates were shown in Table 1. Conclusion Nivolumab at 1 mg/kg cohort is well tolerated and has encouraging clinical efficacy for advanced or relapsed, platinum-resistant ovarian cancer patients. 3 mg/kg cohort is now under investigation. (Table Presented). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody nivolumab platinum EMTREE DRUG INDEX TERMS ligand receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female genital tract cancer human immunotherapy ovary cancer phase 2 clinical trial society EMTREE MEDICAL INDEX TERMS adverse drug reaction antineoplastic activity cancer patient death disease control disease course disorientation examination female fever gait patient safety T lymphocyte tumor immunity LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71681188 DOI 10.1097/01.IGC.0000457075.08973.89 FULL TEXT LINK http://dx.doi.org/10.1097/01.IGC.0000457075.08973.89 COPYRIGHT Copyright 2014 Elsevier B.V., All rights reserved. RECORD 132 TITLE Immunreactivity for CTLA-4 in anterior pituitary gland cells and neutrophils suggest antibody dependent cytotoxicity to trigger Ipilimumab induced hypophysitis AUTHOR NAMES Bjasch D. Marquez Maggio E. Fitsche A. Moch H. Goldinger S.M. Dummer R. Mihic-Probst D. AUTHOR ADDRESSES (Marquez Maggio E.; Fitsche A.; Moch H.; Goldinger S.M.; Dummer R.; Mihic-Probst D.) (Bjasch D.) Universitiy Hospital, Surgical Pathology, Zürich, Switzerland. CORRESPONDENCE ADDRESS D. Bjasch, Universitiy Hospital, Surgical Pathology, Zürich, Switzerland. SOURCE Virchows Archiv (2014) 465:1 SUPPL. 1 (S187-S188). Date of Publication: August 2014 CONFERENCE NAME 26th European Congress of Pathology of the European Society of Pathology, ESP 2014 CONFERENCE LOCATION London, United Kingdom CONFERENCE DATE 2014-08-30 to 2014-09-03 ISSN 0945-6317 BOOK PUBLISHER Springer Verlag ABSTRACT Objective: CTLA-4 is considered as a checkpoint inhibitory receptor during T cell activation. Ipilimumab, a fully human IgG1 mAb, specifically blocks CTLA-4-dependent Tcell inhibition. Ipilimumab therapy has been approved by the FDA based on improved survival of advanced melanoma patients Hypophysitis is frequent adverse reaction, which is postulated to be immune related. Method:We report an autopsy from a patient treated with ipilimumab for metastatic melanoma with clinical and laboratory signs of hypophysitis. The hypophysis was studied using immunohistochemistry for lymphohistiocytic markers including CTLA-4 anti-bodies. Nine pituitary glands without a diagnosis of hypophysitis were also stained. Results: We found numerous spotty necrosis with granulocytic reaction as pathological correlate to the clinically diagnosed hypophysitis. There was no lympho-histiocytic infiltration. Instead we found strong positivity for CTLA-4, especially in the acidophil cells of the anterior pituitary gland. The neurohypophysis was negative for CTLA-4. The autopsy showed much more tumor progression than clinically suspected with multiple mets to the heart. Conclusion: Our finding with positivity for CTLA-4 in eosinophil anterior pituitary gland cells, the numerous spotty necroses with granulocytic reaction, and the absence of lympho-histiocytic infiltration suggests an antibody-dependent cytotoxicity as a possiblemechanismfor hypophysitis. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody cytotoxic T lymphocyte antigen 4 ipilimumab EMTREE DRUG INDEX TERMS marker receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adenohypophysis cytotoxicity hypophysis cell hypophysitis neutrophil pathology society EMTREE MEDICAL INDEX TERMS adverse drug reaction autopsy diagnosis eosinophil food and drug administration heart human hypophysis immunohistochemistry laboratory melanoma metastatic melanoma necrosis neurohypophysis patient survival T lymphocyte activation therapy tumor growth LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71593729 DOI 10.1007/s00428-014-1618-2 FULL TEXT LINK http://dx.doi.org/10.1007/s00428-014-1618-2 COPYRIGHT Copyright 2014 Elsevier B.V., All rights reserved. RECORD 133 TITLE Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer AUTHOR NAMES Hamanishi J. Mandai M. Ikeda T. Minami M. Kawaguchi A. Matsumura N. Abiko K. Baba T. Yamaguchi K. Ueda A. Kanai M. Mori Y. Matsumoto S. Murayama T. Chikuma S. Morita S. Yokode M. Shimizu A. Honjo T. Konishi I. AUTHOR ADDRESSES (Hamanishi J.; Mandai M.; Ikeda T.; Minami M.; Kawaguchi A.; Matsumura N.; Abiko K.; Baba T.; Yamaguchi K.; Ueda A.; Kanai M.; Mori Y.; Matsumoto S.; Murayama T.; Chikuma S.; Morita S.; Yokode M.; Shimizu A.; Honjo T.; Konishi I.) Kyoto University, Kyoto, Japan; Kinki University, Osaka, Japan; Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan CORRESPONDENCE ADDRESS J. Hamanishi, SOURCE Journal of Clinical Oncology (2014) 32:15 SUPPL. 1. Date of Publication: 20 May 2014 CONFERENCE NAME 2014 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2014-05-30 to 2014-06-03 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Programmed death-1 (PD-1) is a co-inhibitory receptor expressed on activated T cells which regulates antitumor immunity. Nivolumab is a fully-humanized IgG4 that blocks the engagement of PD-1 by PD-1 ligands. Here we report the first trial for clinical application of nivolumab in ovarian cancer patients. Methods: Nivolumab was administered every 2 weeks to patients with advanced or relapsed, platinum-resistant ovarian cancer, at the doses of 1 or 3 mg/kg during two cohort examination (10 patients each). The phase II efficacy trial defined 1st endpoint of response rate, and second endpoints of safety, and disease control rate. Patients receivednivolumab up to 6 cycles (4 doses/cycle) of treatment or until PD or disease progression. Response rate was assessed by RECIST v1.1, and adverse events were evaluated by CTCAE v4.0. The data were cut-off on January 1, 2014. Results: Fifteen patients were treated with nivolumab (1 mg/kg: n=10, 3mg/kg: n=5), and evaluated. Median duration of therapy was 14 wks. There was one patient who had severe adverse drug reaction with fever, disorientation and gait disturbance. Clinical response rates were shown in Table. At the time of data cut off, one of the three partial responders had responses for 5 months, and the other two were on study with response for 4 and 10 months. Conclusions:Nivolumab at 1 mg/kg cohort is well tolerated and has encouraging clinical efficacy for advanced or relapsed, platinum-resistant ovarian cancer patients. 3 mg/kg cohort is now under investigation. (Table presented). EMTREE DRUG INDEX TERMS (MAJOR FOCUS) antibody nivolumab platinum EMTREE DRUG INDEX TERMS ligand receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) female human oncology ovary cancer patient safety society EMTREE MEDICAL INDEX TERMS adverse drug reaction cancer patient death disease control disease course disorientation examination fever gait immunity T lymphocyte treatment duration LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71524512 COPYRIGHT Copyright 2014 Elsevier B.V., All rights reserved. RECORD 134 TITLE Exploiting the defective p53/MDM2/p14(ARF) pathway in neuroblastoma by targeting checkpoint kinase Chk1 with AZD7762 AUTHOR NAMES Xu H. Wei X. Cheung I.Y. Cheung N.-K.V. AUTHOR ADDRESSES (Xu H.; Wei X.; Cheung I.Y.; Cheung N.-K.V.) Memorial Sloan-Kettering Cancer Center, New York, United States. CORRESPONDENCE ADDRESS H. Xu, Memorial Sloan-Kettering Cancer Center, New York, United States. SOURCE Cancer Research (2010) 70:8 SUPPL. 1. Date of Publication: 15 Apr 2010 CONFERENCE NAME 101st Annual Meeting of the American Association for Cancer Research, AACR 2010 CONFERENCE LOCATION Washington, DC, United States CONFERENCE DATE 2010-04-17 to 2010-04-21 ISSN 0008-5472 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Introduction: A defective p53/MDM2/p14(ARF) pathway seems to be the principal mode of checkpoint dysfunction in metastatic neuroblastoma following DNA damage, which probably accounts for chemoresistance after initial treatment response. Checkpoint kinase inhibitor AZD7762 (AstraZeneca, currently in clinical trials) has the potential to enhance the action of DNA-damaging agents in some advanced solid malignancies. In this study, we assessed the potential synergy between AZD7762 and chemotherapeutic agents in the in vitro and in vivo treatment of neuroblastoma cells which harbor aberrations in the p53/MDM2/p14(ARF) pathway. Experimental Design: AZD7762 was tested in combination with chemotherapeutic agents both in vitro and in vivo against a representative panel of neuroblastoma cell lines. Ten were p53/MDM2/p14(ARF) pathway-defective (four with p53 mutations, three with MDM2 amplification, and three with p14(ARF) deletion) and three were wild type. Using these lines, p53/p21 functional assay, drug induced cytotoxicity, S/G2 checkpoint abrogation, and therapy of xenografts were examined. Synergism with chemotherapy was quantified using combination index (CI). CI<1 indicates synergism, CI=1 additive effects, and CI>1 antagonism. Results: Based on p53/p21 functional assays, all four p53 mutant lines failed to show endogenous p21 induction after DNA damage (defined as p53 pathway nonfunctional). Similarly, p53 was nonfunctional in two of the three MDM2 amplified and one of the three p14(ARF) deleted cell lines. In cytotoxicity assays, p53 nonfunctional lines were more resistant to DNA-damaging agents when compared to p53 functional lines. Synergy between AZD7762 and DNA-damaging agents (cisplatin, doxorubicin, etoposide, melphalan, SN38 and topotecan) was strong in all p53 nonfunctional lines (average CI values: 0.44 - 0.63), but not in p53 functional lines (average CI values greater than 1.0). In contrast, gemcitabine showed even stronger synergy with AZD7762 regardless of p53 functional status (CI values: 0.11 - 0.47). AZD7762 treatment resulted in the abrogation of DNA damage-induced S/G2 checkpoint arrest, and in the potentiation of antitumor activity of DNA-damaging agents in four mouse xenograft models. Conclusions: AZD7762 potentiated both in vitro and in vivo the antitumor effects of DNA-damaging agents against neuroblastoma. These results suggest that the addition of AZD7762 may reverse or prevent drug resistance, especially if a defective p53/MDM2/p14(ARF) pathway is the underlying mechanism. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) 5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide checkpoint kinase 1 EMTREE DRUG INDEX TERMS antiinfective agent cisplatin DNA doxorubicin etoposide firtecan gemcitabine melphalan phosphotransferase inhibitor protein p53 topotecan EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer research neuroblastoma EMTREE MEDICAL INDEX TERMS antineoplastic activity assay cell line chemotherapy clinical trial (topic) cytotoxicity cytotoxicity assay DNA damage drug resistance experimental design functional status in vitro study model mouse mutant mutation neuroblastoma cell neuroblastoma cell line S phase cell cycle checkpoint solid therapy treatment response wild type xenograft LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71454471 DOI 10.1158/1538-7445.AM10-5408 FULL TEXT LINK http://dx.doi.org/10.1158/1538-7445.AM10-5408 COPYRIGHT Copyright 2014 Elsevier B.V., All rights reserved. RECORD 135 TITLE Sixth cranial nerve palsy as an unusual presenting symptom of ipilimumab-induced hypophysitis AUTHOR NAMES Burgess D. Loh K.P. Lee S.Y. Ali S. AUTHOR ADDRESSES (Burgess D.; Loh K.P.; Lee S.Y.; Ali S.) Baystate Medical Center, Springfield, United States. CORRESPONDENCE ADDRESS D. Burgess, Baystate Medical Center, Springfield, United States. SOURCE Journal of General Internal Medicine (2013) 28 SUPPL. 1 (S390-S391). Date of Publication: June 2013 CONFERENCE NAME 36th Annual Meeting of the Society of General Internal Medicine, SGIM 2013 CONFERENCE LOCATION Denver, CO, United States CONFERENCE DATE 2013-04-24 to 2013-04-27 ISSN 0884-8734 BOOK PUBLISHER Springer New York ABSTRACT LEARNING OBJECTIVE 1: Recognize ipilimumab as a recently approved drug for the treatment of metastatic melanoma LEARNING OBJECTIVE 2: Recognize hypophysitis as a common immunological side-effect of ipilimumab CASE: A 72-year-old man presented with progressively worsening diplopia, associated with headache and fatigue. He denied any associated focal neurological weakness, parasthesias, facial droop, aphasia, fever, neck stiffness, nausea, or vomiting. Physical examination revealed medial deviation of his right eye. The rest of his neurological exam was unremarkable. No orbital swelling or erythema was noted. His medical history was notable for stage IIB malignant melanoma which was resected with sentinel lymph node biopsy. Due to high risk of recurrence, he was enrolled in the ECOG 1609 trial and was randomized to ipilimumab therapy. He had completed 3 cycles of therapy prior to admission. On admission his vitals were within normal limits. Laboratory investigations revealed evidence of hypopituitarism; he had significant hyponatremia, subclinical hypothyroidism, hypoprolactinemia, and low ACTH, LH and cortisol. MRI of the brain showed an asymmetrically enlarged pituitary gland without any evidence of extraocular pathology, suggesting cranial nerve compression as the cause of his diplopia. The patient was subsequently given IV corticosteroids, with rapid improvement of his diplopia, headache and hyponatremia. DISCUSSION: Until recently, dacarbazine and high-dose interleukin- 2 were the only therapies approved by the US Food and Drug Administration (FDA) for metastatic melanoma. However, in March of 2011, ipilimumab became the newest agent for this indication and is the only drug that has shown a clear survival benefit in clinical trials. This case is interesting in that it underscores the atypical presentation of ipilimumab-induced hypophysitis. Ipilimumab is a human monoclonal antibody directed against the cytotoxic T-lymphocyte antigen-4 receptor, thus enhancing T-cell activation and amplifying T-cell-mediated immunity. The most common side effects are autoimmune and include hypophysitis, dermatitis and colitis. Hypophysitis usually manifests as headache and/or symptoms of pituitary hormone deficiency. Ocular side effects are much less common, although there have been reports of extraocular muscle deficits associated with ipilimumab due to orbital myositis. In our patient, there was no evidence of extraocular myositis. His unusual presentation with diplopia was caused by compression of his sixth cranial nerve as it ran laterally to the enlarged pituitary gland; a direct result of ipilimumabinduced hypophysitis. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS corticosteroid corticotropin cytotoxic T lymphocyte antigen 4 dacarbazine human monoclonal antibody hydrocortisone hypophysis hormone interleukin 2 receptor EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) abducens nerve cranial nerve paralysis hypophysitis internal medicine society EMTREE MEDICAL INDEX TERMS aphasia brain cellular immunity clinical trial (topic) colitis compression cranial nerve dermatitis diplopia drug megadose electrocorticography erythema extraocular muscle eye fatigue fever food and drug administration headache hormone deficiency human hyponatremia hypophysis hypopituitarism laboratory male medical history melanoma metastatic melanoma myositis nausea neck nerve compression nuclear magnetic resonance imaging orbit tumor orbital myositis pathology patient physical examination rigidity risk sentinel lymph node biopsy side effect subclinical hypothyroidism survival T lymphocyte T lymphocyte activation therapy vomiting weakness LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71293540 COPYRIGHT Copyright 2014 Elsevier B.V., All rights reserved. RECORD 136 TITLE Endocrine toxicities after treatment with ipilimumab AUTHOR NAMES Zovato S. Sartorato P. Camozzi V. Chiarion V. Pigozzo J. Faoro S. Opocher G. AUTHOR ADDRESSES (Zovato S.; Sartorato P.; Camozzi V.; Opocher G.) Veneto Institute of Oncology IOV, IRCCS, Familiar Cancer Clinic- Oncologic Endocrinology, Padova, Italy. (Chiarion V.; Pigozzo J.) Veneto Institute of Oncology IOV, IRCCS, Medical Oncology-IOV-Padova, Padova, Italy. (Faoro S.) Veneto Institute of Oncology IOV, IRCCS, Pharmacy-IOV-Padova, Padova, Italy. CORRESPONDENCE ADDRESS S. Zovato, Veneto Institute of Oncology IOV, IRCCS, Familiar Cancer Clinic- Oncologic Endocrinology, Padova, Italy. SOURCE European Journal of Cancer (2013) 49 SUPPL. 2 (S872). Date of Publication: September 2013 CONFERENCE NAME European Cancer Congress 2013, ECC 2013 CONFERENCE LOCATION Amsterdam, Netherlands CONFERENCE DATE 2013-09-27 to 2013-10-01 ISSN 0959-8049 BOOK PUBLISHER Elsevier Ltd ABSTRACT Background: Ipilimumab (IPL) is a MAB directed against the CTLA-4 which promotes activation of cytotoxic lymphocytes and augments an immunemediated anti-tumour response. IPL is now licensed for the treatment of unresectable or metastatic malignant melanoma. A host of immunerelated adverse events are associated with the anti CTLA-4 therapy. The endocrinologist may be involved in the management of IPL treated patients in whom may arise secondary hypophysitis with hypopituitarism in 1-6 % of patients, followed by hypo-and hyperthyroidism secondary to thyroiditis in 2.7 and 0.3%, respectively and primary adrenal insufficiency in 2.1%. Patients and Methods: We studied 8 patients (age: 51±7; M/F:6/2) with metastatic melanoma enrolles in different trials with IPL. They presented hypophysitis symptoms after a median time of 11 weeks (range 7-16). All patients presented fatigue and asthenia and 4 also severe headache. Results: All 8 patients had biochemical evidence of secondary adrenal insufficiency (median random cortisol level 105 ±112 nmol/L with undetectable ACTH levels); four patients presented also low FT3 (mean 2.86 pmol/L) and FT4 levels (mean 11.1 pmol/L) with low TSH in 3 cases (mean 0.245 mU/L) and in normal range in one (2.59 mU/L). 3 male patients also presented with a severe deficiency of testosterone (6±3 nmol/L). Three cases had also very low values of IGF-1 (65±22ug/L). One patient had the MRI which documented diffuse enlargement of the pituitary gland. All patients, as required by trial safety procedures, started with prednison 1 to 2 mg/kg orally once per day with gradual tapering and then substituted with cortison acetate. 3 patients also started thyroxine treatment.1 patient experienced a concomitant autoimmune hyperthyroidism that still requires thyrostatic treatment. Long term follow-up of our patients (11±8 months after IPL discontinuation) showed a persistent need for glucocorticoid replacement, while 2 patients recovered the thyroid axis function after 4 months from hypothyroidism and 2 patients the gonadal axis after 2 months. Conclusion: The prevalence of IPL induced hypopituitarism may be higher than that previously thought and the effects on adrenal axis may be irreversible. This emphasizes the clinical relevance of endocrine toxicity and the importance of warning for early screening of pituitary insufficiencies in these patients. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS acetic acid antithyroid agent corticotropin cortisone cytotoxic T lymphocyte antigen 4 glucocorticoid hydrocortisone prednisone testosterone thyrotropin thyroxine EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) neoplasm toxicity EMTREE MEDICAL INDEX TERMS adrenal gland adrenal insufficiency asthenia cytotoxic lymphocyte endocrinologist fatigue follow up headache human hyperthyroidism hypophysis hypophysitis hypopituitarism hypothyroidism male melanoma metastatic melanoma nuclear magnetic resonance imaging oral drug administration patient prevalence procedures safety screening therapy thyroid gland thyroiditis LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71219638 DOI 10.1016/S0959-8049(13)70065-0 FULL TEXT LINK http://dx.doi.org/10.1016/S0959-8049(13)70065-0 COPYRIGHT Copyright 2013 Elsevier B.V., All rights reserved. RECORD 137 TITLE Hyponatremia and hypopituitarism secondary to Ipilimumab AUTHOR NAMES Leonard D. Desai U. AUTHOR ADDRESSES (Leonard D.; Desai U.) Florida Hospital Internal Medicine Residency, Orlando, United States. CORRESPONDENCE ADDRESS D. Leonard, Florida Hospital Internal Medicine Residency, Orlando, United States. SOURCE American Journal of Kidney Diseases (2013) 61:4 (A59). Date of Publication: April 2013 CONFERENCE NAME National Kidney Foundation 2013 Spring Clinical Meetings CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2013-04-02 to 2013-04-06 ISSN 0272-6386 BOOK PUBLISHER W.B. Saunders ABSTRACT Ipilimumab is a monoclonal antibody that enhances T-cell activation and proliferation and is utilized in the treatment of unresectable or metastatic melanoma . Here we present a rare combination of side effects secondary to this medication: hyponatremia and hypopituitarism. A 76 year old Caucasian female with a past medical history of metastatic melanoma, mitral valve prolapse, and hyperlipidemia presents with a headache, nausea, vomiting and altered mental status for 5 days. Home medications include Atenolol and Simvastatin and Ipilimumab which was started two months ago at a dose of 3 mg/kg Q 3 weeks. Her last dose was on August 17. On September 5, she was found to have a sodium of 118 mMol/L secondary to SI ADH, a TSH of 0.095 microIU/mL, T4 of 3.2 mcg/dL, Cortisol of 1.5 mcg/dL, and low values of FSH and LH. MRI showed pituitary enlargement measuring 1.1 cm after increasing 6-7mm. She was treated by correcting volume status and administering thyroid replacement, and steroids with improvement. The etiology was attributed to Ipilimumab induced hypophysitis with secondary central hypopituitarism, Hypopituitarism is a well-known side-effect of Ipilimumab, however hyponatremia is not listed among the side effects of this medication in most literature. One product monograph by Bristol-Myers Squibb Canada lists hyponatremia as a potential adverse effect in 0.1 -< 1 %. Literature review is very scant in terms of case reports on the matter. One case report by Barnard et al. illustrates the relationship between hyponatremia and Ipilimumab -induced hypophysitis, however this is the extent to which this serious side effect has been reported. In conclusion, it is of the utmost importance to spread awareness of this growing and life threatening side effect profile that can be discovered in a timely fashion and treated through early detection techniques. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS atenolol follitropin hydrocortisone monoclonal antibody simvastatin sodium steroid thyrotropin vasopressin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hyponatremia hypopituitarism kidney non profit organization EMTREE MEDICAL INDEX TERMS adverse drug reaction book Canada case report Caucasian drug therapy etiology female headache human hyperlipidemia hypophysis hypophysitis medical history mental health metastatic melanoma mitral valve prolapse nausea nuclear magnetic resonance imaging side effect T lymphocyte activation thyroid gland vomiting LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71023999 DOI 10.1053/j.ajkd.2013.02.180 FULL TEXT LINK http://dx.doi.org/10.1053/j.ajkd.2013.02.180 COPYRIGHT Copyright 2013 Elsevier B.V., All rights reserved. RECORD 138 TITLE Ipilimumab-induced hypophysitis in melanoma patients AUTHOR NAMES Carrã T. Caroline G.-M. Albarel F. Monestier S. Mallet S. Brue T. Richard M.-A. Grob J.J. AUTHOR ADDRESSES (Carrã T.; Caroline G.-M.; Albarel F.; Monestier S.; Mallet S.; Brue T.; Richard M.-A.; Grob J.J.) Dermatology Department, Timone Hospital, Aix Marseille University, Marseille, France; Hôpital Timone, Aix Marseille University, Marseille, France; Endocrinology Department, Timone Hospital, Aix-Marseille University, Marseille, France; Hopital Timone, Aix-Marseille University, Marseille, France; Hopital Timone, Aix-Marseille Universiy, Marseille, France; Endocrinology Department, Timone Hospital, Aix-Marseille Université, Marseille, France; Timone Hospital, Aix-Marseille University, Marseille, France; Dermatology Department, Timone Hospital, Aix-Marseille University, Marseille, France CORRESPONDENCE ADDRESS T. Carrã, SOURCE Journal of Clinical Oncology (2012) 30:15 SUPPL. 1. Date of Publication: 20 May 2012 CONFERENCE NAME 2012 Annual Meeting of the American Society of Clinical Oncology, ASCO CONFERENCE LOCATION Chicago, IL, United States CONFERENCE DATE 2012-06-01 to 2012-06-05 ISSN 0732-183X BOOK PUBLISHER American Society of Clinical Oncology ABSTRACT Background: Ipilimumab (Ipi) is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for the treatment of metastatic melanoma (MM) and currently under investigation in the adjuvant setting. Methods: Retrospective analysis of patients treated with ipi between June 2006 and September 2011 in our department in Marseille. As some patients are still blinded in trials, the exact number of patient under ipi is unknown. We present a minimal percentage (>%) assuming that the 120 patients received ipi. Results: A total of 120 patients were treated: 76 stages IV MM, from which 16 in the BMS clinical trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 or 10mg/kg IV dosage, while stages III MM were randomly assigned to receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 patients (>10%): 2/76 patients with stage IV MM (>2. 6 %) and 10/44 patients with stage III MM (>22.7). Diagnosis was performed at the 1(st), 3(rd) and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients (33.3%). Clinical symptoms included headaches (n=11; 91.6%), asthenia (n=7; 58.3%) and decreased libido (n=2; 1.6%). Adrenal, thyroidal and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 patients (58.3%). MRI changes were observed in 7 patients (58.3%): pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids supplementation was required in 11 patients and thyroidian supplementation in 4 patients. Clinical symptoms regressed within one week in 8 patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only if clinicians are aware of these unspecific signs. Only MRI can make diagnosis in some patients without clinical and/or biological signs. Our data suggest that it develops especially for 10mg/kg dosage, after the third administration, and that the rate could be higher in patients with a normal immune system (adjuvant treatment), than in metastatic ones. Hormonal supplementation usually controls the disease. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS adjuvant corticosteroid human monoclonal antibody placebo EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) human hypophysitis melanoma oncology patient society EMTREE MEDICAL INDEX TERMS adjuvant therapy adrenal gland asthenia clinical trial (topic) cytotoxic T lymphocyte diagnosis headache hypophysis immune system libido disorder metastatic melanoma nuclear magnetic resonance imaging supplementation swelling LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L71004918 COPYRIGHT Copyright 2013 Elsevier B.V., All rights reserved. RECORD 139 TITLE Low-dose conformal radiation therapy for ipilimumab-induced hypophysitis AUTHOR NAMES Menzel P.L. Geng A. Marquez C. Scala M. Minor D. Abendroth R. AUTHOR ADDRESSES (Menzel P.L.; Geng A.; Marquez C.; Minor D.; Abendroth R.) California Pacific Medical Center, San Francisco, United States. (Scala M.) Memorial Sloan-Kettering Cancer Center, New York, United States. CORRESPONDENCE ADDRESS P.L. Menzel, California Pacific Medical Center, San Francisco, United States. SOURCE International Journal of Radiation Oncology Biology Physics (2012) 84:3 SUPPL. 1 (S279). Date of Publication: 1 Nov 2012 CONFERENCE NAME 54th Annual Meeting of the American Society for Radiation Oncology, ASTRO 2012 CONFERENCE LOCATION Boston, MA, United States CONFERENCE DATE 2012-10-28 to 2012-10-31 ISSN 0360-3016 BOOK PUBLISHER Elsevier Inc. ABSTRACT Purpose/Objective(s): Ipilimumab is an immunostimulatory anti-CTLA 4 antibody that has been shown to improve survival in patients with metastatic melanoma. Unfortunately, 10-15% of patients treated with ipilimumab develop hypophysitis, which is often treated with systemic steroids or ipilimumab cessation or dose reduction. As these treatments are not optimal for patients who may be responding to ipilimumab, we present here our initial experience treating ipilimumab-induced hypophysitis with low-dose conformal radiation therapy. Materials/Methods: This is a single institution retrospective review of metastatic melanoma patients with ipilimumab-induced hypophysitis who were treated with low-dose pituitary radiation therapy. All patients had biochemical evidence of pituitary dysfunction and MRI features of hypophysitis, including diffuse pituitary enlargement and enhancement. Radiation therapy was linear accelerator-based and consisted of three daily 150 cGy fractions delivered using 6- or 15-MV photons. The PTV consisted of the pituitary gland and a 0.5-1 cm margin, which was treated via a three or five field conformal plan. A thermoplastic mask was employed for immobilization. Clinical follow-up as well as pre- and post-treatment MRIs were used to evaluate treatment efficacy, with pituitary volumes calculated using the volumetric formula for an ellipsoid (4/3 x p x R1 x R2 x R3). Mean pre- and post-radiation therapy pituitary volumes were compared using the Student's t-test. Results: Between September 10, 2010 and February 24, 2012, seven patients (3 women, 4 men) with a median age of 65 years (range, 39-88) were treated. At a median follow-up of 31 weeks (range, 1-77), no patients experienced acute radiation therapy toxicity or developed new symptoms following treatment. Mean pre- and post-radiation therapy pituitary volumes were 796.7 (range, 433.1-962.5) and 380.8 (range, 266.8-569.7) mm3, respectively (p = 0.005). Radiation therapy was delivered over a median of 5 days (range, 3-5) and without interruption in any patient. All patients who presented with generalized symptoms of fatigue, anorexia, and headache reported symptomatic improvement following treatment. Every patient who presented with a hormonal deficiency had persistent endocrine dysfunction at last follow-up. Conclusion: Low-dose conformal radiation therapy results in significant clinical improvement and radiographic response in patients with ipilimumab- induced hypophysitis, although there is no amelioration of endocrine dysfunction following treatment. This treatment represents a promising therapeutic option for patients with ipilimumab-induced hypophysitis whose survival may be adversely affected by treatment with systemic steroids or interference of ipilimumab administration. Additional exploration and follow-up is necessary to determine whether early treatment initiation can reverse endocrine dysfunction. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS cytotoxic T lymphocyte antigen 4 cytotoxic T lymphocyte antigen 4 antibody steroid EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis low drug dose oncology radiotherapy society EMTREE MEDICAL INDEX TERMS anorexia drug dose reduction endocrine disease fatigue female follow up headache human hypophysis immobilization linear accelerator male metastatic melanoma nuclear magnetic resonance imaging patient photon Student t test survival therapy toxicity LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L70913138 DOI 10.1016/j.ijrobp.2012.07.727 FULL TEXT LINK http://dx.doi.org/10.1016/j.ijrobp.2012.07.727 COPYRIGHT Copyright 2012 Elsevier B.V., All rights reserved. RECORD 140 TITLE Central adrenal insufficiency and hypothyroidism after ipilimumab treatment AUTHOR NAMES Kwun S. Lukacova-Zib I. Gopalakrishnan G. AUTHOR ADDRESSES (Kwun S.; Lukacova-Zib I.; Gopalakrishnan G.) Alpert Medical School, Brown University East, Providence, United States. CORRESPONDENCE ADDRESS S. Kwun, Alpert Medical School, Brown University East, Providence, United States. SOURCE Endocrine Reviews (2012) 33:3 MeetingAbstracts. Date of Publication: June 2012 CONFERENCE NAME 94th Annual Meeting and Expo of the Endocrine Society, ENDO 2012 CONFERENCE LOCATION Houston, TX, United States CONFERENCE DATE 2012-06-23 to 2012-06-26 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT Introduction: Ipilimumab is a targeted antibody that activates a T cell mediated immune response against tumor cells or other antigens. It is used in the treatment of various cancers including metastatic melanoma. Immune reactions to self antigens result in a wide array of adverse events including enterocolitis, hepatitis and endocrinopathies. Although Ipilimumab induced endocrinopathies are rare, the consequences can be severe and typically occur 10 weeks after treatment initiation. We report a case of Ipilimumab induced autoimmune hypophysitis presenting 4 weeks after initial therapy.Clinical Case: A 48 year old female with metastatic melanoma presents with severe headache approximately 4 weeks after initiating Ipilimumab. MRI identified an enlarged pituitary gland measuring 1.2 cm in the craniocaudal dimension. Prior imaging was notable for a normal pituitary gland measuring 5.4 mm. Pituitary enhancement was suspicious for lymphocytic hypophysitis or metastatic disease. The patient was continued on Ipilimumab and placed on high dose steroids to treat the autoimmune process. Evaluation of pituitary function was notable for a TSH 0.3 (0.35-5.50 uIU/ml), FT4 0.73(0.8-1.8ng/d.), Cortisol AM 0.7 (6.2 to 19.4ug/dl), Prolactin 1(3-29ng/ml) and IGF-1 85 (118-298ng/ml) suggesting hypopituitarism. The patient was treated with thyroid hormone replacement and the steroid dose was tapered to maintenance levels upon resolution of headache symptoms. Subsequent imaging showed a stable, non-FDG avid pituitary lesion on PET-CT. Conclusion : The autoimmune effects of Ipilimumab may lead to hypophysitis and other endocrinopathies. Since adverse events can occur early in the treatment course, we recommend clinical evaluations to focus on the pituitary, adrenal and thyroid axis after each treatment cycle and with symptoms. Laboratory and brain imaging can be considered based on clinical assessments. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS antibody antigen hydrocortisone prolactin steroid thyroid hormone thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) adrenal insufficiency hypothyroidism society EMTREE MEDICAL INDEX TERMS adrenal gland brain cellular immunity clinical assessment clinical evaluation drug megadose enterocolitis female headache hepatitis hormone substitution human hypophysis hypophysis function hypophysitis hypopituitarism imaging immunity laboratory metastasis metastatic melanoma neoplasm nuclear magnetic resonance imaging patient T lymphocyte thyroid gland tumor cell LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L70834515 COPYRIGHT Copyright 2012 Elsevier B.V., All rights reserved. RECORD 141 TITLE Ipilimumab-associated hypophysitis-time course of MRI and hormonal changes AUTHOR NAMES Eranki V.G. Elhomsy G. Silverberg A. Albert S. AUTHOR ADDRESSES (Eranki V.G.; Elhomsy G.; Silverberg A.; Albert S.) Division of Endocrinology, Saint Louis University, School of Medicine, St Louis, United States. CORRESPONDENCE ADDRESS V.G. Eranki, Division of Endocrinology, Saint Louis University, School of Medicine, St Louis, United States. SOURCE Endocrine Reviews (2012) 33:3 MeetingAbstracts. Date of Publication: June 2012 CONFERENCE NAME 94th Annual Meeting and Expo of the Endocrine Society, ENDO 2012 CONFERENCE LOCATION Houston, TX, United States CONFERENCE DATE 2012-06-23 to 2012-06-26 ISSN 0163-769X BOOK PUBLISHER Endocrine Society ABSTRACT IntroductionIpilimumab (Yervoy), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, is approved for chemotherapy of metastatic melanoma. This antibody augments T-cell activation, proliferation and anti-tumor immunity. Adverse effects include immune-mediated endocrinopathies. We report the natural history of Ipilimumab associated hypophysitis.Clinical CaseA 76 year old man with melanoma diagnosed three years previously had undergone surgical resection, radiation and chemotherapy. With tumor recurrence in the lungs, Ipilimumab was instituted at 3 mg/kg every three weeks for four doses. Four weeks after completing the regimen, he presented with severe fatigue, headache and blurry vision. Blood pressure was 127/79 without orthostatic changes. There was no hyper-pigmentation. Visual fields and ophthalmological funduscopic examinations were normal.Laboratory tests: TSH <0.015 μIU/mL (0.35-5.5), free T4 <0.4 ng/dL (0.7-1.9), ACTH 2.5 pg/mL (7.2-63), and diminished response to cosyntropin stimulation test (CST) [baseline serum cortisol (Ct0) <0.2 μg/dL (4.3-28) and 1-hour(Ct1) 6.8 μg/dL]. MRI showed a hyper-enhancing pituitary gland (volume = 900 mm3) which was distinctly different from the pre-therapy MRI, which was non-enhancing (volume = 354 mm3). The patient was diagnosed with hypophysitis and treated with prednisone (5mg/day) and levothyroxine. Five months later, there was resolution of the hyper-intense pituitary uptake (pituitary volume = 115 mm3). Repeat endocrine evaluation was: TSH = 0.19 μIU/mL, ACTH <1.1pg/mL and CST with (Ct0) = 0.2μg/dL, (Ct1) = 3.0 μg/dL.Discussion/ConclusionThe patient presented with symptoms which may have been ascribed to tumor cachexia. Endocrine and neuro imaging evaluation confirmed hypophysitis. Five months after discontinuation of the drug, there was a reversal of the hypophysitis on MRI but not in recovery of ACTH. Although, it is suggested that the hypophysitis be treated with high dose steroids, the patient received a physiological replacement dose in an attempt not to reverse the immunological anticancer effects. Ipilimumab induced hypophysitis should be evaluated with appropriate hormonal and MR imaging in a patient with 'tumor cachexia'. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) ipilimumab EMTREE DRUG INDEX TERMS antibody corticotropin cytotoxic T lymphocyte antigen 4 levothyroxine monoclonal antibody prednisone steroid tetracosactide thyrotropin EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) hypophysitis nuclear magnetic resonance imaging society EMTREE MEDICAL INDEX TERMS adverse drug reaction blood pressure cachexia chemotherapy drug megadose examination fatigue headache history human hydrocortisone blood level hyperpigmentation hypophysis imaging lung male melanoma metastatic melanoma neoplasm patient provocation test radiation surgery T lymphocyte activation therapy tumor immunity tumor recurrence visual field LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L70834514 COPYRIGHT Copyright 2012 Elsevier B.V., All rights reserved. RECORD 142 TITLE Inhibition of checkpoint kinase 1 (Chk1) as a potential therapeutic for pediatric neuroblastoma AUTHOR NAMES Russell M.R. Cole K.A. Maris J.M. AUTHOR ADDRESSES (Russell M.R.; Cole K.A.; Maris J.M.) Children's Hospital of Philadelphia, Philadelphia, United States. CORRESPONDENCE ADDRESS M.R. Russell, Children's Hospital of Philadelphia, Philadelphia, United States. SOURCE Cancer Research (2011) 71:8 SUPPL. 1. Date of Publication: 15 Apr 2011 CONFERENCE NAME 102nd Annual Meeting of the American Association for Cancer Research, AACR 2011 CONFERENCE LOCATION Orlando, FL, United States CONFERENCE DATE 2011-04-02 to 2011-04-06 ISSN 0008-5472 BOOK PUBLISHER American Association for Cancer Research Inc. ABSTRACT Neuroblastoma is a cancer derived from cells of the sympathetic nervous system that manifests with significant clinical heterogeneity. Although children diagnosed with low-risk neuroblastoma are very likely to be cured, high-risk patients are frequently resistant to even the most intensive of multi-modal regimens, and at least half of these children suffer relapse that is almost always fatal. To address the unmet need for novel therapeutic targets, our lab conducted an unbiased siRNA screen and determined that the loss of cell cycle checkpoint kinase 1 (Chk1) produced the most robust cytotoxic effect across multiple neuroblastoma cell lines. We subsequently confirmed that many neuroblastoma cell lines express constitutively phosphorylated Chk1 - a discovery that is supported by identical findings in tumors obtained from high-risk patients. Here we present evidence that the combination of a small molecule inhibitor of Chk1 with either irinotecan (SN-38) or cisplatin was synergistic or additive in vitro in cell lines sensitive to single agent Chk1 inhibition. Inhibition of Chk1 signaling as potential therapy in neuroblastoma is further supported by complimentary experiments in which we found that induction of shRNA specific for Chk1 results in marked cytotoxicity. To further understand the chemosensitizing aspect of Chk1 inhibition in neuroblastoma cells, we assayed the ATR/Chk1 pathway for potential biomarkers predictive of response. Candidate signaling partners in this pathway were isolated based upon either pharmacological inhibition or shRNA-induced silencing of Chk1, followed by hybridization to antibody microarrays. This technique has allowed for identification of Chk1-related signaling proteins involved in the DNA damage response pathway. Lastly, we have assessed the efficacy of Chk1 inhibition in an in vivo xenograft mouse model of pediatric neuroblastoma. We found that daily administration of a small molecule Chk1 inhibitor, currently undergoing Phase I clinical testing, was able to significantly impede the growth of NB1643 neuroblastoma xenografts (p=0.001). Efforts are currently underway in our laboratory to investigate a potentially synergistic effect in vivo through co-administration of this inhibitor with irinotecan or cisplatin. Taken together, these results provide a strong rationale for further studies to assess the use of Chk1 inhibition as either a single-agent or combinatorial therapy in pediatric neuroblastoma. EMTREE DRUG INDEX TERMS (MAJOR FOCUS) checkpoint kinase 1 EMTREE DRUG INDEX TERMS antibody cisplatin DNA irinotecan protein short hairpin RNA small interfering RNA EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS) cancer research neuroblastoma EMTREE MEDICAL INDEX TERMS adrenergic system cell cycle checkpoint cell line child cytotoxicity DNA damage high risk patient human hybridization in vitro study laboratory model mouse neoplasm neoplasm neuroblastoma cell relapse risk therapy xenograft LANGUAGE OF ARTICLE English LANGUAGE OF SUMMARY English PUI L70688172 DOI 10.1158/1538-7445.AM2011-4758 FULL TEXT LINK http://dx.doi.org/10.1158/1538-7445.AM2011-4758 COPYRIGHT Copyright 2012 Elsevier B.V., All rights reserved.