Download PDF
Horm Metab Res 2019; 51(03): 145-156
DOI: 10.1055/a-0843-3366
Review
© Georg Thieme Verlag KG Stuttgart · New York

A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors

Jeroen de Filette
1   Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
,
Corina Emilia Andreescu
1   Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
,
Filip Cools
2   Department of Neonatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
,
Bert Bravenboer
1   Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
,
Brigitte Velkeniers
1   Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
› Author Affiliations
Further Information

Publication History

received 11 June 2018

accepted 22 January 2019

Publication Date:
12 March 2019 (online)

Also available at
   Permissions and Reprints

Abstract

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9–8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2–1.2) and pembrolizumab (1.1%; 95% CI, 0.5–2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction – particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4–9.8; pembrolizumab, 8.5%; 95% CI, 7.5–9.7; PD-L1, 5.5%; 95% CI, 4.4–6.8; ipilimumab, 3.8%; 95% CI, 2.6–5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2–16.4%), hyperthyroidism (9.4–10.4%), hypophysitis (8.8–10.5%), and primary adrenal insufficiency (5.2–7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

Key words

hypophysitis - thyroiditis - CTLA-4 - PD-1 - PD-L1

Supplementary Material

 

  • References

  • 1 U.S. Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications.May 26 2017 Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm Accessed June 5, 2017
    PubMed
  • 2 Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 8th Edition Philadelphia, PA: Elsevier Saunders; 2015
    Search in Google Scholar
  • 3 Byun DJ, Wolchok JD, Rosenberg LM. et al. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 2017; 13: 195-207
    CrossrefPubMedSearch in Google Scholar
  • 4 Barroso-Sousa R, Barry WT, Garrido-Castro AC. et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: A systematic review and meta-analysis. JAMA Oncol 2018; 4: 173-182
    CrossrefPubMedSearch in Google Scholar
  • 5 Wang PF, Chen Y, Song SY. et al. Immune-related adverse events associated with anti-PD-1/PD-l1 treatment for malignancies: A meta-analysis. Front Pharmacol 2017; 8: 730
    CrossrefPubMedSearch in Google Scholar
  • 6 Shang YH, Zhang Y, Li JH. et al. Risk of endocrine adverse events in cancer patients treated with PD-1 inhibitors: A systematic review and meta-analysis. Immunotherapy 2017; 9: 261-272
    CrossrefPubMedSearch in Google Scholar
  • 7 Abdel-Rahman O, ElHalawani H, Fouad M. Risk of endocrine complications in cancer patients treated with immune check point inhibitors: A meta-analysis. Future Oncol (London, England) 2016; 12: 413-425
    CrossrefPubMedSearch in Google Scholar
  • 8 Ascierto PA, Del Vecchio M, Robert C. et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: A Randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2017; 18: 611-622
    CrossrefPubMedSearch in Google Scholar
  • 9 Bang YJ, Cho JY, Kim YH. et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res 2017; 23: 5671-5678
    CrossrefPubMedSearch in Google Scholar
  • 10 Brilli L, Danielli R, Ciuoli C. et al. Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab. Endocrine 2017; 58: 535-541
    CrossrefPubMedSearch in Google Scholar
  • 11 Jung M, Lee J, Kim TM. et al. Ipilimumab real-world efficacy and safety in korean melanoma patients from the korean named-patient program cohort. Cancer Res Treat 2017; 49: 44-53
    CrossrefPubMedSearch in Google Scholar
  • 12 Schachter J, Ribas A, Long GV. et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet (London, England) 2017; 390: 1853-1862
    CrossrefPubMedSearch in Google Scholar
  • 13 Wen X, Ding Y, Li J. et al. The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: A retrospective case series. Cancer Immunol Immunother 2017; 66: 1153-1162
    CrossrefPubMedSearch in Google Scholar
  • 14 Boudewijns S, Koornstra RH, Westdorp H. et al. Ipilimumab administered to metastatic melanoma patients who progressed after dendritic cell vaccination. Oncoimmunology 2016; 5: e1201625
    CrossrefPubMedSearch in Google Scholar
  • 15 Eggermont AM, Chiarion-Sileni V, Grob JJ. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016; 375: 1845-1855
    CrossrefPubMedSearch in Google Scholar
  • 16 Hodi FS, Chesney J, Pavlick AC. et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016; 17: 1558-1568
    CrossrefPubMedSearch in Google Scholar
  • 17 Larkin J, Chiarion-Sileni V, Gonzalez R. et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373: 23-34
    CrossrefPubMedSearch in Google Scholar
  • 18 Min L, Hodi FS, Giobbie-Hurder A. et al. Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: A retrospective cohort study. Clin Cancer Res 2015; 21: 749-755
    CrossrefPubMedSearch in Google Scholar
  • 19 Yamazaki N, Kiyohara Y, Uhara H. et al. Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma. Cancer Chemother Pharmacol 2015; 76: 997-1004
    CrossrefPubMedSearch in Google Scholar
  • 20 Yamazaki N, Uhara H, Fukushima S. et al. Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma. Cancer Chemother Pharmacol 2015; 76: 969-975
    CrossrefPubMedSearch in Google Scholar
  • 21 Zimmer L, Eigentler TK, Kiecker F. et al. Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma. J Transl Med 2015; 13: 351
    CrossrefPubMedSearch in Google Scholar
  • 22 Zimmer L, Vaubel J, Mohr P. et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naive patients with metastatic uveal melanoma. PloS One 2015; 10: e0118564
    CrossrefPubMedSearch in Google Scholar
  • 23 Alexander M, Mellor JD, McArthur G. et al. Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma. Med J Australia 2014; 201: 49-53
    PubMedSearch in Google Scholar
  • 24 Chiarion-Sileni V, Pigozzo J, Ascierto PA. et al. Ipilimumab retreatment in patients with pretreated advanced melanoma: The expanded access programme in Italy. Brit Journal Cancer 2014; 110: 1721-1726
    PubMedSearch in Google Scholar
  • 25 Faje AT, Sullivan R, Lawrence D. et al. Ipilimumab-induced hypophysitis: A Detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 2014; 99: 4078-4085
    CrossrefPubMedSearch in Google Scholar
  • 26 Kwon ED, Drake CG, Scher HI. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700-712
    CrossrefPubMedSearch in Google Scholar
  • 27 Ryder M, Callahan M, Postow MA. et al. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: A comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014; 21: 371-381
    CrossrefPubMedSearch in Google Scholar
  • 28 Altomonte M, Di Giacomo A, Queirolo P. et al. Clinical experience with ipilimumab 10 mg/kg in patients with melanoma treated at Italian centres as part of a European expanded access programme. J Exp Clin Cancer Res 2013; 32: 82
    CrossrefPubMedSearch in Google Scholar
  • 29 Delyon J, Mateus C, Lefeuvre D. et al. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: An early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 2013; 24: 1697-1703
    CrossrefPubMedSearch in Google Scholar
  • 30 Luke JJ, Callahan MK, Postow MA et al. Clinical activity of ipilimumab for metastatic uveal melanoma: A retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013: 119: 3687–3695
  • 31 Postow MA, Luke JJ, Bluth MJ. et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013; 18: 726-732
    CrossrefPubMedSearch in Google Scholar
  • 32 Robert C, Thomas L, Bondarenko I. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517-2526
    CrossrefPubMedSearch in Google Scholar
  • 33 Hodi FS, O'Day SJ, McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-723
    CrossrefPubMedSearch in Google Scholar
  • 34 Ku GY, Yuan J, Page DB. et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: Lymphocyte count after 2 doses correlates with survival. Cancer 2010; 116: 1767-1775
    CrossrefPubMedSearch in Google Scholar
  • 35 Royal RE, Levy C, Turner K. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother (Hagerstown, Md: 1997) 2010; 33: 828-833
    CrossrefPubMedSearch in Google Scholar
  • 36 Downey SG, Klapper JA, Smith FO. et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 2007; 13: 6681-6688
    CrossrefPubMedSearch in Google Scholar
  • 37 Maker AV, Yang JC, Sherry RM. et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. Journal of immunotherapy (Hagerstown, Md: 1997) 2006; 29: 455-463
    CrossrefPubMedSearch in Google Scholar
  • 38 Maio M, Scherpereel A, Calabro L. et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): A multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol 2017; 18: 1261-1273
    CrossrefPubMedSearch in Google Scholar
  • 39 Joshua AM, Monzon JG, Mihalcioiu C. et al. A phase 2 study of tremelimumab in patients with advanced uveal melanoma. Melanoma Res 2015; 25: 342-347
    CrossrefPubMedSearch in Google Scholar
  • 40 Aglietta M, Barone C, Sawyer MB. et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol 2014; 25: 1750-1755
    CrossrefPubMedSearch in Google Scholar
  • 41 Ribas A, Kefford R, Marshall MA. et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013; 31: 616-622
    CrossrefPubMedSearch in Google Scholar
  • 42 Chung KY, Gore I, Fong L. et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol 2010; 28: 3485-3490
    CrossrefPubMedSearch in Google Scholar
  • 43 Kirkwood JM, Lorigan P, Hersey P. et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res 2010; 16: 1042-1048
    CrossrefPubMedSearch in Google Scholar
  • 44 Camacho LH, Antonia S, Sosman J. et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol 2009; 27: 1075-1081
    CrossrefPubMedSearch in Google Scholar
  • 45 Ribas A, Camacho LH, Lopez-Berestein G. et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005; 23: 8968-8977
    CrossrefPubMedSearch in Google Scholar
  • 46 Carbone DP, Reck M, Paz-Ares L. et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med 2017; 376: 2415-2426
    CrossrefPubMedSearch in Google Scholar
  • 47 El-Khoueiry AB, Sangro B, Yau T. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet (London, England) 2017; 389: 2492-2502
    CrossrefPubMedSearch in Google Scholar
  • 48 Larkin J, Minor D, D'Angelo S. et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in checkmate 037: A randomized, controlled, open-label phase III trial. J Clin Oncol 2018; 36: 383-390
    PubMedSearch in Google Scholar
  • 49 Maruyama D, Hatake K, Kinoshita T. et al. A multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Cancer Sci 2017; 108: 1007-1012
    CrossrefPubMedSearch in Google Scholar
  • 50 Morris VK, Salem ME, Nimeiri H. et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18: 446-453
    CrossrefPubMedSearch in Google Scholar
  • 51 Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182-1191
    CrossrefPubMedSearch in Google Scholar
  • 52 Sharma P, Retz M, Siefker-Radtke A. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18: 312-322
    CrossrefPubMedSearch in Google Scholar
  • 53 Yamazaki N, Kiyohara Y, Uhara H. et al. Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study. Cancer Sci 2017; 108: 1223-1230
    CrossrefPubMedSearch in Google Scholar
  • 54 Yamazaki N, Kiyohara Y, Uhara H. et al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase II study for advanced melanoma. Cancer Sci 2017; 108: 1022-1031
    CrossrefPubMedSearch in Google Scholar
  • 55 Antonia SJ, Lopez-Martin JA, Bendell J. et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016; 17: 883-895
    CrossrefPubMedSearch in Google Scholar
  • 56 Choueiri TK, Fishman MN, Escudier B. et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin Cancer Res 2016; 22: 5461-5471
    CrossrefPubMedSearch in Google Scholar
  • 57 Ferris RL, Blumenschein Jr. G, Fayette J. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375: 1856-1867
    CrossrefPubMedSearch in Google Scholar
  • 58 Gettinger S, Rizvi NA, Chow LQ. et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016; 34: 2980-2987
    CrossrefPubMedSearch in Google Scholar
  • 59 Rizvi NA, Hellmann MD, Brahmer JR. et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2016; 34: 2969-2979
    CrossrefPubMedSearch in Google Scholar
  • 60 Sharma P, Callahan MK, Bono P. et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): A multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 2016; 17: 1590-1598
    CrossrefPubMedSearch in Google Scholar
  • 61 Weber J, Gibney G, Kudchadkar R. et al. Phase I/II Study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol Res 2016; 4: 345-353
    CrossrefPubMedSearch in Google Scholar
  • 62 Ansell SM, Lesokhin AM, Borrello I. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372: 311-319
    CrossrefPubMedSearch in Google Scholar
  • 63 Borghaei H, Paz-Ares L, Horn L. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373: 1627-1639
    CrossrefPubMedSearch in Google Scholar
  • 64 Brahmer J, Reckamp KL, Baas P. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123-135
    CrossrefPubMedSearch in Google Scholar
  • 65 Hamanishi J, Mandai M, Ikeda T. et al. Safety and antitumor activity of anti-pd-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol 2015; 33: 4015-4022
    CrossrefPubMedSearch in Google Scholar
  • 66 McDermott DF, Drake CG, Sznol M. et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 2015; 33: 2013-2020
    CrossrefPubMedSearch in Google Scholar
  • 67 Motzer RJ, Rini BI, McDermott DF. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase ii trial. J Clin Oncol 2015; 33: 1430-1437
    CrossrefPubMedSearch in Google Scholar
  • 68 Rizvi NA, Mazieres J, Planchard D. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol 2015; 16: 257-265
    CrossrefPubMedSearch in Google Scholar
  • 69 Robert C, Long GV, Brady B. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320-330
    CrossrefPubMedSearch in Google Scholar
  • 70 Weber JS, D'Angelo SP, Minor D. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A Randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16: 375-384
    CrossrefPubMedSearch in Google Scholar
  • 71 Topalian SL, Sznol M, McDermott DF. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32: 1020-1030
    CrossrefPubMedSearch in Google Scholar
  • 72 Bauml J, Seiwert TY, Pfister DG. et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase ii study. J Clin Oncol 2017; 35: 1542-1549
    CrossrefPubMedSearch in Google Scholar
  • 73 Bellmunt J, de Wit R, Vaughn DJ. et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 1015-1026
    CrossrefPubMedSearch in Google Scholar
  • 74 Chen R, Zinzani PL, Fanale MA. et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic hodgkin lymphoma. J Clin Oncol 2017; 35: 2125-2132
    CrossrefPubMedSearch in Google Scholar
  • 75 Delivanis DA, Gustafson MP, Bornschlegl S. et al. Pembrolizumab-induced thyroiditis: comprehensive clinical review and insights into underlying involved mechanisms. J Clin Endocrinol Metab 2017; 102: 2770-2780
    CrossrefPubMedSearch in Google Scholar
  • 76 Ott PA, Piha-Paul SA, Munster P. et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 2017; 28: 1036-1041
    CrossrefPubMedSearch in Google Scholar
  • 77 Ott PA, Elez E, Hiret S. et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase ib keynote-028 study. J Clin Oncol 2017; 35: 3823-3829
    CrossrefPubMedSearch in Google Scholar
  • 78 Yamazaki N, Takenouchi T, Fujimoto M. et al. Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). Cancer Chemother Pharmacol 2017; 79: 651-660
    CrossrefPubMedSearch in Google Scholar
  • 79 Zinzani PL, Ribrag V, Moskowitz CH. et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood 2017; 130: 267-270
    CrossrefPubMedSearch in Google Scholar
  • 80 Armand P, Shipp MA, Ribrag V. et al. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol 2016; 34: 3733-3739
    CrossrefPubMedSearch in Google Scholar
  • 81 Chatterjee M, Turner DC, Felip E. et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol 2016; 27: 1291-1298
    CrossrefPubMedSearch in Google Scholar
  • 82 Chow LQ, Haddad R, Gupta S. et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase ib keynote-012 expansion cohort. J Clin Oncol 2016; 34: 3838-3845
    CrossrefPubMedSearch in Google Scholar
  • 83 de Filette J, Jansen Y, Schreuer M. et al. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab. J Clin Endocrinol Metab 2016; 101: 4431-4439
    CrossrefPubMedSearch in Google Scholar
  • 84 Langer CJ, Gadgeel SM, Borghaei H. et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A Randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 17: 1497-1508
    CrossrefPubMedSearch in Google Scholar
  • 85 Muro K, Chung HC, Shankaran V. et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial. Lancet Oncol 2016; 17: 717-726
    CrossrefPubMedSearch in Google Scholar
  • 86 Nanda R, Chow LQ, Dees EC. et al. Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol 2016; 34: 2460-2467
    CrossrefPubMedSearch in Google Scholar
  • 87 Reck M, Rodriguez-Abreu D, Robinson AG. et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375: 1823-1833
    CrossrefPubMedSearch in Google Scholar
  • 88 Ribas A, Hamid O, Daud A. et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 2016; 315: 1600-1609
    CrossrefPubMedSearch in Google Scholar
  • 89 Seiwert TY, Burtness B, Mehra R. et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 2016; 17: 956-965
    CrossrefPubMedSearch in Google Scholar
  • 90 Herbst RS, Baas P, Kim DW. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A Randomised controlled trial. Lancet (London, England) 2016; 387: 1540-1550
    CrossrefPubMedSearch in Google Scholar
  • 91 Garon EB, Rizvi NA, Hui R. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: 2018-2028
    CrossrefPubMedSearch in Google Scholar
  • 92 Patnaik A, Kang SP, Rasco D. et al. Phase I study of pembrolizumab (MK-3475; Anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 4286-4293
    CrossrefPubMedSearch in Google Scholar
  • 93 Ribas A, Puzanov I, Dummer R. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A Randomised, controlled, phase 2 trial. Lancet Oncol 2015; 16: 908-918
    CrossrefPubMedSearch in Google Scholar
  • 94 Robert C, Ribas A, Wolchok JD. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A Randomised dose-comparison cohort of a phase 1 trial. Lancet (London, England) 2014; 384: 1109-1117
    CrossrefPubMedSearch in Google Scholar
  • 95 Balar AV, Galsky MD, Rosenberg JE. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A Single-arm, multicentre, phase 2 trial. Lancet (London, England) 2017; 389: 67-76
    CrossrefPubMedSearch in Google Scholar
  • 96 Peters S, Gettinger S, Johnson ML. et al. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J Clin Oncol 2017; 35: 2781-2789
    CrossrefPubMedSearch in Google Scholar
  • 97 Fehrenbacher L, Spira A, Ballinger M. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet (London, England) 2016; 387: 1837-1846
    CrossrefPubMedSearch in Google Scholar
  • 98 McDermott DF, Sosman JA, Sznol M. et al. Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. J Clin Oncol 2016; 34: 833-842
    CrossrefPubMedSearch in Google Scholar
  • 99 Apolo AB, Infante JR, Balmanoukian A. et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol 2017; 35: 2117-2124
    CrossrefPubMedSearch in Google Scholar
  • 100 Gulley JL, Rajan A, Spigel DR. et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): Dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017; 18: 599-610
    CrossrefPubMedSearch in Google Scholar
  • 101 Kaufman HL, Russell J, Hamid O. et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016; 17: 1374-1385
    CrossrefPubMedSearch in Google Scholar
  • 102 Powles T, O'Donnell PH, Massard C. et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 2017; 3: e172411
    CrossrefPubMedSearch in Google Scholar
  • 103 Hellmann MD, Rizvi NA, Goldman JW. et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 2017; 18: 31
    CrossrefPubMedSearch in Google Scholar
  • 104 Hammers HJ, Plimack ER, Infante JR. et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: The CheckMate 016 Study. J Clin Oncol 2017; 35: 38513858
    PubMedSearch in Google Scholar
  • 105 Shoushtari AN, Friedman CF, Navid-Azarbaijani P. et al. Measuring toxic effects and time to treatment failure for nivolumab plus ipilimumab in melanoma. JAMA Oncol 2018; 4: 98-101
    CrossrefPubMedSearch in Google Scholar
  • 106 Wolchok JD, Kluger H, Callahan MK. et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122-133
    CrossrefPubMedSearch in Google Scholar
  • 107 Long GV, Atkinson V, Cebon JS. et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 2017; 18: 1202-1210
    CrossrefPubMedSearch in Google Scholar
  • 108 Antonia S, Goldberg SB, Balmanoukian A. et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 2016; 17: 299-308
    CrossrefPubMedSearch in Google Scholar
  • 109 Araujo PB, Coelho MC, Arruda M. et al. Ipilimumab-induced hypophysitis: Review of the literature. J Endocrinol Invest 2015; 38: 1159-1166
    CrossrefPubMedSearch in Google Scholar
  • 110 Corsello SM, Barnabei A, Marchetti P. et al. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013; 98: 1361-1375
    CrossrefPubMedSearch in Google Scholar
  • 111 Bertrand A, Kostine M, Barnetche T. et al. Immune related adverse events associated with anti-CTLA-4 antibodies: Systematic review and meta-analysis. BMC Medicine 2015; 13: 211
    CrossrefPubMedSearch in Google Scholar
  • 112 Albarel F, Gaudy C, Castinetti F. et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol 2015; 172: 195-204
    CrossrefPubMedSearch in Google Scholar
  • 113 Blansfield JA, Beck KE, Tran K. et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother (Hagerstown, Md: 1997) 2005; 28: 593-598
    CrossrefPubMedSearch in Google Scholar
  • 114 Dillard T, Yedinak CG, Alumkal J. et al. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: Serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 2010; 13: 29-38
    CrossrefPubMedSearch in Google Scholar
  • 115 Iwama S, De Remigis A, Callahan MK. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 2014; 6: 230ra245
    PubMedSearch in Google Scholar
  • 116 Caturegli P, Di Dalmazi G, Lombardi M. et al. Hypophysitis secondary to cytotoxic t-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol 2016; 186: 3225-3235
    CrossrefPubMedSearch in Google Scholar
  • 117 Blomhoff A, Lie BA, Myhre AG. et al. Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease. J Clin Endocrinol Metab 2004; 89: 3474-3476
    CrossrefPubMedSearch in Google Scholar
  • 118 Ueda H, Howson JM, Esposito L. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506-511
    CrossrefPubMedSearch in Google Scholar
  • 119 Orlov S, Salari F, Kashat L. et al. Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab 2015; 100: 1738-1741
    CrossrefPubMedSearch in Google Scholar
  • 120 Alhusseini M, Samantray J. Hypothyroidism in cancer patients on immune checkpoint inhibitors with anti-PD1 Agents: Insights on underlying mechanisms. Exp Clin Endocrinol Diabetes 2017; 125: 267-269
    Thieme ConnectPubMedSearch in Google Scholar
  • 121 van Kooten MJ, van den Berg G, Glaudemans A. et al. Transient thyrotoxicosis during nivolumab treatment. Netherl J Med 2017; 75: 204-207
    PubMedSearch in Google Scholar
  • 122 Azmat U, Liebner D, Joehlin-Price A. et al. Treatment of ipilimumab induced graves' disease in a patient with metastatic melanoma. Case Rep Endocrinol 2016; 2087525
    PubMedSearch in Google Scholar
  • 123 Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 2011; 164: 303-307
    CrossrefPubMedSearch in Google Scholar
  • 124 Gan EH, Mitchell AL, Plummer R. et al. Tremelimumab-Induced Graves Hyperthyroidism. Eur Thyr J 2017; 6: 167-170
    PubMedSearch in Google Scholar
  • 125 Andersen TB, Aleksyniene R, Gormsen LC. et al. Effect of recent contrast-enhanced CT and patient age on image quality of thyroid scintigraphy. Clin Nucl Med 2015; 40: 297-302
    CrossrefPubMedSearch in Google Scholar
  • 126 McMillen B, Dhillon MS, Yong-Yow S. A rare case of thyroid storm. BMJ Case Rep 2016; 2016;
    CrossrefPubMedSearch in Google Scholar
  • 127 Morganstein DL, Lai Z, Spain L. et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol 2017; 86: 614-620
    CrossrefPubMedSearch in Google Scholar
  • 128 Yamauchi I, Sakane Y, Fukuda Y. et al. Clinical features of nivolumab-induced thyroiditis: A case series study. Thyroid 2017; 27: 894-901
    CrossrefPubMedSearch in Google Scholar
  • 129 Angell TE, Lechner MG, Jang JK. et al. BRAF V600E in papillary thyroid carcinoma is associated with increased programmed death ligand 1 expression and suppressive immune cell infiltration. Thyroid 2014; 24: 1385-1393
    CrossrefPubMedSearch in Google Scholar
  • 130 Chintakuntlawar AV, Rumilla KM, Smith CY. et al. Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study. J Clin Endocrinol Metab 2017; 102: 1943-1950
    CrossrefPubMedSearch in Google Scholar
  • 131 Newby PR, Roberts-Davies EL, Brand OJ. et al. Tag SNP screening of the PDCD1 gene for association with Graves' disease. Clin Endocrinol 2007; 67: 125-128
    CrossrefPubMedSearch in Google Scholar
  • 132 Hayashi M, Kouki T, Takasu N. et al. Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients. Eur J Endocrinol 2008; 158: 817-822
    CrossrefPubMedSearch in Google Scholar
  • 133 Kobayashi T, Iwama S, Yasuda Y. et al. Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: A prospective study. J Endocr Soc 2018; 2: 241-251
    CrossrefPubMedSearch in Google Scholar
  • 134 Moeller LC, Fuhrer D. Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer 2013; 20: R19-R29
    CrossrefPubMedSearch in Google Scholar
  • 135 Theodossiou C, Skrepnik N, Robert EG. et al. Propylthiouracil-induced hypothyroidism reduces xenograft tumor growth in athymic nude mice. Cancer 1999; 86: 1596-1601
    CrossrefPubMedSearch in Google Scholar
  • 136 Fabian ID, Rosner M, Fabian I. et al. Low thyroid hormone levels improve survival in murine model for ocular melanoma. Oncotarget 2015; 6: 11038-11046
    CrossrefPubMedSearch in Google Scholar
  • 137 Kinoshita S, Sone S, Yamashita T. et al. Effects of experimental hyper- and hypothyroidism on natural defense activities against Lewis lung carcinoma and its spontaneous pulmonary metastases in C57BL/6 mice. Tokushima J Exp Med 1991; 38: 25-35
    PubMedSearch in Google Scholar
  • 138 Baldazzi V, Tassi R, Lapini A. et al. The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: A prospective single-center study. Urol Oncol 2012; 30: 704-710
    CrossrefPubMedSearch in Google Scholar
  • 139 Clemons J, Gao D, Naam M. et al. Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer 2012; 10: 225-231
    CrossrefPubMedSearch in Google Scholar
  • 140 Weijl NI, Van der Harst D, Brand A. et al. Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J Clin Oncol 1993; 11: 1376-1383
    CrossrefPubMedSearch in Google Scholar
  • 141 Hercbergs A, Johnson RE, Ashur-Fabian O. et al. Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: An Observational study. Oncologist 2015; 20: 72-76
    CrossrefPubMedSearch in Google Scholar
  • 142 Matsumura K, Nagasawa K, Oshima Y. et al. Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant HLA DRB1*15:02 treated with nivolumab. J Diabetes Invest 2017; 9: 438-441
    PubMedSearch in Google Scholar
  • 143 Hughes J, Vudattu N, Sznol M. et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 2015; 38: e55-e57
    PubMedSearch in Google Scholar
  • 144 Okamoto M, Okamoto M, Gotoh K. et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Invest 2016; 7: 915-918
    CrossrefPubMedSearch in Google Scholar
  • 145 Lowe JR, Perry DJ, Salama AK. et al. Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. J Immunother Cancer 2016; 4: 89
    CrossrefPubMedSearch in Google Scholar
  • 146 Fujisawa R, Haseda F, Tsutsumi C. et al. Low programmed cell death-1 (PD-1) expression in peripheral CD4(+) T cells in Japanese patients with autoimmune type 1 diabetes. Clin Exp Immunol 2015; 180: 452-457
    CrossrefPubMedSearch in Google Scholar
  • 147 Perri V, Russo B, Crino A. et al. Expression of pd-1 molecule on regulatory t lymphocytes in patients with insulin-dependent diabetes mellitus. Int J Mol Sci 2015; 16: 22584-22605
    CrossrefPubMedSearch in Google Scholar
  • 148 Luczynski W, Wawrusiewicz-Kurylonek N, Stasiak-Barmuta A. et al. Diminished expression of ICOS, GITR and CTLA-4 at the mRNA level in T regulatory cells of children with newly diagnosed type 1 diabetes. Acta Biochim Pol 2009; 56: 361-370
    PubMedSearch in Google Scholar
  • 149 Haseda F, Imagawa A, Murase-Mishiba Y. et al. Low CTLA-4 expression in CD4+helper T-cells in patients with fulminant type 1 diabetes. Immunol Lett 2011; 139: 80-86
    CrossrefPubMedSearch in Google Scholar
  • 150 Paepegaey AC, Lheure C, Ratour C. et al. Polyendocrinopathy resulting from pembrolizumab in a patient with a malignant melanoma. J Endocr Soc 2017; 1: 646-649
    CrossrefPubMedSearch in Google Scholar
  • 151 Min L, Ibrahim N. Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol 2013; 1: e15
    CrossrefPubMedSearch in Google Scholar
  • 152 Trainer H, Hulse P, Higham CE. et al. Hyponatraemia secondary to nivolumab-induced primary adrenal failure. Endocrinol Diabetes Metab Case Reps 2016; 2016 pii 16-0108 [Epub 2016 Nov 1]
    PubMedSearch in Google Scholar
  • 153 Win MA, Thein KZ, Qdaisat A. et al. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Am J Emerg Med 2017; 35: 1039 e1035-1039 e1037
    PubMedSearch in Google Scholar
  • 154 Horinouchi H, Yamamoto N, Fujiwara Y. et al. Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. Invest New Drugs 2015; 33: 881-889
    CrossrefPubMedSearch in Google Scholar
  • 155 Wahab IA, Pratt NL, Kalisch LM. et al. The detection of adverse events in randomized clinical trials: Can we really say new medicines are safe?. Curr Drug Safety 2013; 8: 104-113
    CrossrefPubMedSearch in Google Scholar
  • 156 National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE).Version 4.03.; June 14 2010 Available at https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_4.03.xlsx Accessed March 27, 2018
    PubMed