Incidence and Management of Immune-Related Adverse Events in Patients Undergoing Treatment with Immune Checkpoint Inhibitors

  • Lisa A. Kottschade
Palliative Medicine (A Jatoi, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Palliative Medicine


Purpose of Review

The unleashing of the immune system in an effort to fight cancer has proven to be an incredible advance in the war on cancer. However that breakthrough has come with a price in the form of serious and potentially fatal immune-related adverse events (irAEs).

Recent Findings

Rapid recognition and early intervention is imperative to avoid significant morbidity and mortality. Additionally, providers need to be aware that there are still new, rare, and long-term emerging irAEs that were not previously reported in clinical trials.


Because of the significant difference between irAEs and those caused by chemotherapy and/or targeted therapy, providers must have a thorough understanding of which events would be considered immune related and require treatment. This review will cover descriptions of the most common and uncommon but serious irAEs experienced by patients on immunotherapy, as well as management of these irAEs.


Cancer Immunotherapy Immune checkpoint inhibitors Immune-related adverse events 


Compliance with Ethical Standards

Conflict of Interest

Lisa A. Kottschade has received research support through a grant from Bristol-Myers Squibb (paid to Mayo Clinic) and has served as a consultant for Genentech (compensation paid to Mayo Clinic).

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312(17):1744–53. Scholar
  2. 2.
    Hodi FS, O’Day SJ, DF MD, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. Scholar
  3. 3.
    McDermott D, Lebbe C, Hodi FS, Maio M, Weber JS, Wolchok JD, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40(9):1056–64. Scholar
  4. 4.
    Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300–9. CrossRefPubMedGoogle Scholar
  5. 5.
    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82. Scholar
  6. 6.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. Scholar
  7. 7.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26. Scholar
  8. 8.
    Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22. Scholar
  9. 9.
    • Sznol M, Ferrucci PF, Hogg D, Atkins MB, Wolter P, Guidoboni M, et al. Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma. J Clin Oncol. 2017;JCO2016721167. Largest pooled analysis to date of irAEs from combination ICI therapy. Google Scholar
  10. 10.
    • Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211. Large review and meta-analysis of irAEs from anti-CTLA-4 therapy. PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grunwald V, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev. 2016;45:7–18. Scholar
  12. 12.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. Scholar
  13. 13.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. Scholar
  14. 14.
    Co. M. Keytruda (pembrolizumab) for injection: Highlights of Prescribing Information. 2014, Accessed April 19, 2015 at
  15. 15.
    Di Giacomo AM, Danielli R, Guidoboni M, Calabro L, Carlucci D, Miracco C, et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother. 2009;58(8):1297–306. Scholar
  16. 16.
    Ibrahim RA, Berman DM, DePril V, Humphrey RW, Chen T, Messina M, et al., editors. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma 2011. J Clin Oncol. 2011.Google Scholar
  17. 17.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. Scholar
  18. 18.
    Lui P, Cashin R, Machado M, Hemels M, Corey-Lisle PK, Einarson TR. Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. 2007;33(8):665–80. Scholar
  19. 19.
    Luke JJ, Ott PA. PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. Oncotarget. 2015;6(6):3479–92. Scholar
  20. 20.
    Mier JW. Checkpoint inhibitors in the treatment of metastatic melanoma. Clin Ther. 2015;37(4):753.CrossRefPubMedGoogle Scholar
  21. 21.
    O’Day S, Weber JS, Wolchok JD, Richards JM, Lorigan P, McDermott DF, et al. Effectiveness of treatment guidance on diarrhea and colitis across ipilimumab studies. J Clin Oncol. 2011; 29(15_suppl):8554.Google Scholar
  22. 22.
    O’Sullivan CG, Madan RA, Gulley JL. Nivolumab: promising survival signal coupled with limited toxicity raises expectations. J Clin Oncol. 2014;32(10):986–8. Scholar
  23. 23.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17. Scholar
  24. 24.
    Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62. Scholar
  25. 25.
    Rivere A, Bourgeois DJ, Riker AI. Use of ipilimumab in melanoma. Immunotherapy. 2011;3(8):927–30. CrossRefPubMedGoogle Scholar
  26. 26.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. Scholar
  27. 27.
    Robert C, Schadendorf D, Messina M, Hodi FS, O’Day S. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res. 2013;19(8):2232–9. Scholar
  28. 28.
    Robinson MR, Chan CC, Yang JC, Rubin BI, Gracia GJ, Sen HN, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother. 2004;27(6):478–9. Scholar
  29. 29.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. Scholar
  30. 30.
    Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64. Scholar
  31. 31.
    Zibelman M, Olszanski AJ. Full spectrum: efficacy and toxicity of immunotherapy in metastatic melanoma. J Natl Compr Cancer Netw. 2014; 12(suppl. 2): S-1–S-5.Google Scholar
  32. 32.
    • Abdel-Rahman O, Oweira H, Petrausch U, Helbling D, Schmidt J, Mannhart M, et al. Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review. Expert Rev Anticancer Ther. 2017;17(4):387–94. Good overview of ocular toxicities which is a rare irAE. CrossRefPubMedGoogle Scholar
  33. 33.
    Akhtari M, Waller EK, Jaye DL, Lawson DH, Ibrahim R, Papadopoulos NE, et al. Neutropenia in a patient treated with ipilimumab (anti-CTLA-4 antibody). J Immunother. 2009;32(3):322–4. Scholar
  34. 34.
    Barjaktarevic IZ, Qadir N, Suri A, Santamauro JT, Stover D. Organizing pneumonia as a side effect of ipilimumab treatment of melanoma. Chest. 2013;143(3):858–61. CrossRefPubMedGoogle Scholar
  35. 35.
    Berthod G, Lazor R, Letovanec I, Romano E, Noirez L, Mazza Stalder J, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30(17):e156–9. Scholar
  36. 36.
    Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet-Froment M, et al. Severe meningo-radiculo-neuritis associated with ipilimumab. Investig New Drugs. 2012;30(6):2407–10. Scholar
  37. 37.
    Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13(4):278–80. Scholar
  38. 38.
    Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98(4):1361–75. Scholar
  39. 39.
    Delyon J, Mateus C, Lambert T. Hemophilia A induced by ipilimumab. N Engl J Med. 2011;365(18):1747–8. CrossRefPubMedGoogle Scholar
  40. 40.
    Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med. 2009;361(2):211–2. Scholar
  41. 41.
    Gonzalez-Rodriguez E, Rodriguez-Abreu D. Spanish Group for Cancer I-B. Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist. 2016;21(7):804–16. Scholar
  42. 42.
    Gordon IO, Wade T, Chin K, Dickstein J, Gajewski TF. Immune-mediated red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma. Cancer Immunol Immunother. 2009;58(8):1351–3. Scholar
  43. 43.
    Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol. 2017:1.
  44. 44.
    Hunter G, Voll C, Robinson CA. Autoimmune inflammatory myopathy after treatment with ipilimumab. Can J Neurol Sci. 2009;36(4):518–20. Scholar
  45. 45.
    Izzedine H, Gueutin V, Gharbi C, Mateus C, Robert C, Routier E, et al. Kidney injuries related to ipilimumab. Investig New Drugs. 2014;32(4):769–73. Scholar
  46. 46.
    Johnson DB, Wallender EK, Cohen DN, Likhari SS, Zwerner JP, Powers JG, et al. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Cancer Immunol Res. 2013;1(6):373–7. Scholar
  47. 47.
    Kim KW, Ramaiya NH, Krajewski KM, Jagannathan JP, Tirumani SH, Srivastava A, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Investig New Drugs. 2013;31(4):1071–7. Scholar
  48. 48.
    Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro-Oncology. 2014;16(4):589–93. Scholar
  49. 49.
    Lozier J. More on hemophilia A induced by ipilimumab. N Engl J Med. 2012;366(3):280–1; author reply 1. Scholar
  50. 50.
    Maur M, Tomasello C, Frassoldati A, Dieci MV, Barbieri E, Conte P. Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. J Clin Oncol. 2012;30(6):e76–8. Scholar
  51. 51.
    Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6. CrossRefPubMedGoogle Scholar
  52. 52.
    • Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014;21(2):371–81. Comprehensive review of endocrine toxicities from ICI therapy. This is an often difficult irAE to diagnose and manage and this article does a good job of defining these toxicities. PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283–9. Scholar
  54. 54.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. Scholar
  55. 55.
    • Kottschade L, Brys A, Peikert T, Ryder M, Raffals L, Brewer J, et al. A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy. Melanoma Res. 2016;26(5):469–80. Good comprehensive overview with algorithms of a multidisciplinary approach to manage irAEs for ICI therapy. CrossRefPubMedGoogle Scholar
  56. 56.
    Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100(8):4712–7. Scholar
  57. 57.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. Scholar
  58. 58.
    Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675–82. Scholar
  59. 59.
    Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9. Scholar
  60. 60.
    Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barre syndrome in a melanoma patient. Ann Oncol. 2011;22(4):991–3. Scholar
  61. 61.
    Gullo L. Day-to-day variations of serum pancreatic enzymes in benign pancreatic hyperenzymemia. Clin Gastroenterol Hepatol. 2007;5(1):70–4. Scholar
  62. 62.
    Chae YK, Chiec L, Mohindra N, Gentzler R, Patel J, Giles F. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol Immunother. 2017;66(1):25–32. Scholar
  63. 63.
    Smith-Cohn MA, Gill D, Voorhies BN, Agarwal N, Garrido-Laguna I. Case report: pembrolizumab-induced type 1 diabetes in a patient with metastatic cholangiocarcinoma. Immunotherapy. 2017;9(10):797–804. Scholar
  64. 64.
    Telo GH, Carvalhal GF, CGS C, Webber VS, Barrios CH, Fay AP. Fulminant type 1 diabetes caused by dual immune checkpoint blockade in metastatic renal cell carcinoma. Ann Oncol. 2017;28(1):191–2. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Oncology—Mayo ClinicRochesterUSA

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