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Immune Checkpoint Inhibitor Toxicity

  • Melanoma (RJ Sullivan, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of review

Immune checkpoint inhibitors have revolutionised the treatment of multiple malignancies and have a growing list of indications. As our familiarity with these agents grows, so does our understanding of their unique spectrum of toxicities. Here, we will review the literature regarding the toxicities of checkpoint inhibitors and address challenges encountered in day-to-day clinical practice.

Recent findings

Inhibitors of the PD-1/PD-L1 axis are considerably less toxic than the anti-CTLA-4 antibody ipilimumab. The combination of ipilimumab and anti-PD-1 agents is being trialled in multiple malignancies and is associated with increased toxicity. There is accumulating evidence suggesting a potential correlation between a subset of toxicities and clinical benefit in several tumour types, although conflicting data exists. Retrospective series have shown that anti-PD-1 can be safely administered to patients with prior high-grade toxicity from ipilimumab or combination immunotherapy.

Summary

The management of checkpoint inhibitor toxicity is complex and requires collaboration with our subspecialty colleagues. Identifying predictive biomarkers of both efficacy and toxicity would likely help guide treatment decisions, and should be a research priority in the years ahead.

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References

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

  1. Hodi FS, O’Day SJ, McDermott DF, 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. • 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. This landmark phase 3 study showed that the anti-PD-1 agent pembrolizumab prolonged PFS and OS and had less high-grade toxicity than ipilimumab in patients with advanced melanoma.

  3. • 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. This landmark phase 3 study showed that the anti-PD-1 nivolumab prolonged PFS (median 5.1 vs 2.2 months) and OS (1-year OS 72.9 vs 42.1%) compared to dacarbazine in patients with metastatic melanoma without a BRAF mutation.

    Article  PubMed  CAS  Google Scholar 

  4. SERVICES. USDOHAH. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 2010 [Available from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03].

  5. • Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56. This large phase 3 study showed that combination therapy with nivolumab plus ipilimumab and monotherapy with nivolumab resulted in significantly longer OS than ipilimumab monotherapy among patients with previously untreated advanced melanoma, albeit with greater treatment-related toxicity (59% grade 3 or 4 AEs) in the combination therapy arm.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. • Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. This is one of two consensus recommendations on the management of irAEs following ICI therapy, developed by a professional working group (SITC).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. • Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119–iv42. This is one of two consensus recommendations on the management of irAEs following ICI therapy, developed by a professional working group (ESMO).

    Article  PubMed  CAS  Google Scholar 

  8. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2016;27(7):1362.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587–98.

    Article  PubMed  CAS  Google Scholar 

  10. Administration. USFaD. Bavencio Prescribing Information 2017 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf.

  11. Lacouture ME, Wolchok JD, Yosipovitch G, Kahler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71(1):161–9.

    Article  PubMed  CAS  Google Scholar 

  12. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. 2017;41(2):125–8.

    Article  PubMed  Google Scholar 

  14. Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74(3):455–61.e1.

    Article  PubMed  Google Scholar 

  15. Hwang SJ, Carlos G, Chou S, Wakade D, Carlino MS, Fernandez-Penas P. Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies. Melanoma Res. 2016;26(4):413–6.

    Article  PubMed  CAS  Google Scholar 

  16. Rivera N, Boada A, Bielsa MI, Fernandez-Figueras MT, Carcereny E, Moran MT, et al. Hair repigmentation during immunotherapy treatment with an anti-programmed cell death 1 and anti-programmed cell death ligand 1 agent for lung cancer. JAMA Dermatol. 2017;153(11):1162–5.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Morganstein DL, Lai Z, Spain L, Diem S, Levine D, Mace C, 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(4):614–20.

    Article  CAS  Google Scholar 

  18. Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28(3):583–9.

    PubMed  CAS  Google Scholar 

  19. • Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 2017. This is the largest published systematic review and meta-analysis of the incidence of endocrine dysfunction following treatment with FDA-approved ICI regimens.

  20. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Torino F, Corsello SM, Salvatori R. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol. 2016;28(4):278–87.

    Article  PubMed  CAS  Google Scholar 

  23. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clin Oncol. 2015;33(18):2092–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab. 2014;99(11):4078–85.

    Article  PubMed  CAS  Google Scholar 

  25. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol. 2017;13(4):195–207.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Min L, Hodi FS, Giobbie-Hurder A, Ott PA, Luke JJ, Donahue H, 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(4):749–55.

    Article  PubMed  CAS  Google Scholar 

  28. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.

    Article  PubMed  CAS  Google Scholar 

  29. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. 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.

    Article  PubMed  CAS  Google Scholar 

  30. Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 2015;38(9):e137–8.

    Article  PubMed  CAS  Google Scholar 

  31. Chmiel KD, Suan D, Liddle C, Nankivell B, Ibrahim R, Bautista C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29(9):e237–40.

    Article  PubMed  CAS  Google Scholar 

  32. Gupta A, De Felice KM, Loftus EV Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015;42(4):406–17.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Marthey L, Mateus C, Mussini C, Nachury M, Nancey S, Grange F, et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohns Colitis. 2016;10(4):395–401.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Messmer M, Upreti S, Tarabishy Y, Mazumder N, Chowdhury R, Yarchoan M, et al. Ipilimumab-induced enteritis without colitis: a new challenge. Case Rep Oncol. 2016;9(3):705–13.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Furst DE, Keystone EC, So AK, Braun J, Breedveld FC, Burmester GR, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Ann Rheum Dis. 2013;72(Suppl 2):ii2–34.

    Article  PubMed  CAS  Google Scholar 

  38. Merrill SP, Reynolds P, Kalra A, Biehl J, Vandivier RW, Mueller SW. Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient. Ann Pharmacother. 2014;48(6):806–10.

    Article  PubMed  CAS  Google Scholar 

  39. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hillock NT, Heard S, Kichenadasse G, Hill CL, Andrews J. Infliximab for ipilimumab-induced colitis: a series of 13 patients. Asia Pac J Clin Oncol. 2017;13(5):e284–e90.

    Article  PubMed  Google Scholar 

  41. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009;24(3):321–5.

    Article  PubMed  CAS  Google Scholar 

  42. Pages C, Gornet JM, Monsel G, Allez M, Bertheau P, Bagot M, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res. 2013;23(3):227–30.

    Article  PubMed  CAS  Google Scholar 

  43. • Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti-programmed Death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709–17. This is the largest published series of pneumonitis following anti-PD-1/PD-L1 agents, and comprehensively characterises the clinical, radiologic and pathologic features as well as management of this entity.

    Article  PubMed  CAS  Google Scholar 

  44. Delaunay M, Cadranel J, Lusque A, Meyer N, Gounant V, Moro-Sibilot D, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J. 2017;50(2):1700050.

    Article  PubMed  Google Scholar 

  45. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.

    Article  PubMed  CAS  Google Scholar 

  46. Lomax AJ, McGuire HM, McNeil C, Choi CJ, Hersey P, Karikios D, et al. Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: case series and immunophenotypic analysis. Int J Rheum Dis. 2017;20(9):1277–85.

    Article  PubMed  CAS  Google Scholar 

  47. Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012;30(2):e7–e10.

    Article  PubMed  Google Scholar 

  48. Suarez-Almazor ME, Kim ST, Abdel-Wahab N, Diab A. Review: immune-related adverse events with use of checkpoint inhibitors for immunotherapy of Cancer. Arthritis Rheumatol. 2017;69(4):687–99.

    Article  PubMed  Google Scholar 

  49. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 2017;76(1):43–50.

    Article  PubMed  CAS  Google Scholar 

  50. Naidoo J, Cappelli LC, Forde PM, Marrone KA, Lipson EJ, Hammers HJ, et al. Inflammatory arthritis: a newly recognized adverse event of immune checkpoint blockade. Oncologist. 2017;22(6):627–30.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Belkhir R, Burel SL, Dunogeant L, Marabelle A, Hollebecque A, Besse B, et al. Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis. 2017;76(10):1747–50.

    Article  PubMed  Google Scholar 

  52. Cappelli LC, Gutierrez AK, Bingham CO, 3rd, Shah AA. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res (Hoboken) 2017; 69(11):1751–1763.

  53. Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:1–8.

    Article  PubMed  CAS  Google Scholar 

  54. Spain L, Walls G, Julve M, O'Meara K, Schmid T, Kalaitzaki E, et al. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol. 2017;28(2):377–85.

    PubMed  CAS  Google Scholar 

  55. Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90(3):638–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Wanchoo R, Karam S, Uppal NN, Barta VS, Deray G, Devoe C, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017;45(2):160–9.

    Article  PubMed  CAS  Google Scholar 

  57. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med. 2009;361(2):211–2.

    Article  PubMed  CAS  Google Scholar 

  58. Murakami N, Motwani S, Riella LV. Renal complications of immune checkpoint blockade. Curr Probl Cancer. 2017;41(2):100–10.

    Article  PubMed  Google Scholar 

  59. 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.

    Article  CAS  Google Scholar 

  60. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Laubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer. 2015;3:11.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Tadokoro T, Keshino E, Makiyama A, Sasaguri T, Ohshima K, Katano H, et al. Acute lymphocytic myocarditis with anti-PD-1 antibody nivolumab. Circ Heart Fail. 2016;9(10):e003514.

    Article  PubMed  Google Scholar 

  63. Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Varricchi G, Galdiero MR, Marone G, Criscuolo G, Triassi M, Bonaduce D, et al. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open. 2017;2(4):e000247.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016;28(4):288–94.

    Article  PubMed  CAS  Google Scholar 

  66. Papavasileiou E, Prasad S, Freitag SK, Sobrin L, Ipilimumab-induced Ocular LAM. Orbital inflammation—a case series and review of the literature. Ocul Immunol Inflamm. 2016;24(2):140–6.

    PubMed  CAS  Google Scholar 

  67. Helgadottir H, Kis L, Ljungman P, Larkin J, Kefford R, Ascierto PA, et al. Lethal aplastic anemia caused by dual immune checkpoint blockade in metastatic melanoma. Ann Oncol. 2017;28(7):1672–3.

    Article  PubMed  CAS  Google Scholar 

  68. Palla AR, Kennedy D, Mosharraf H, Doll D. Autoimmune hemolytic anemia as a complication of nivolumab therapy. Case Rep Oncol. 2016;9(3):691–7.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Delyon J, Mateus C, Lambert T. Hemophilia A induced by ipilimumab. N Engl J Med. 2011;365(18):1747–8.

    Article  PubMed  CAS  Google Scholar 

  70. 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.

    Article  PubMed  Google Scholar 

  71. Pellegrino B, Musolino A, Tiseo M. Anti-PD-1-related cryoglobulinemia during treatment with nivolumab in NSCLC patient. Ann Oncol. 2017;28(6):1405–6.

    Article  PubMed  CAS  Google Scholar 

  72. Kong BY, Micklethwaite KP, Swaminathan S, Kefford RF, Carlino MS. Autoimmune hemolytic anemia induced by anti-PD-1 therapy in metastatic melanoma. Melanoma Res. 2016;26(2):202–4.

    Article  PubMed  CAS  Google Scholar 

  73. Bystryn JC, Rigel D, Friedman RJ, Kopf A. Prognostic significance of hypopigmentation in malignant melanoma. Arch Dermatol. 1987;123(8):1053–5.

    Article  PubMed  CAS  Google Scholar 

  74. Nordlund JJ, Kirkwood JM, Forget BM, Milton G, Albert DM, Lerner AB. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9(5):689–96.

    Article  PubMed  CAS  Google Scholar 

  75. Quaglino P, Marenco F, Osella-Abate S, Cappello N, Ortoncelli M, Salomone B, et al. Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol. 2010;21(2):409–14.

    Article  PubMed  CAS  Google Scholar 

  76. Boasberg PD, Hoon DS, Piro LD, Martin MA, Fujimoto A, Kristedja TS, et al. Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma. J Invest Dermatol. 2006;126(12):2658–63.

    Article  PubMed  CAS  Google Scholar 

  77. Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33(7):773–81.

    Article  PubMed  CAS  Google Scholar 

  78. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of Vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45–51.

    Article  PubMed  Google Scholar 

  79. Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28(6):593–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Arriola E, Wheater M, Karydis I, Thomas G, Ottensmeier C. Infliximab for IPILIMUMAB-related colitis-letter. Clin Cancer Res. 2015;21(24):5642–3.

    Article  PubMed  Google Scholar 

  81. Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33(28):3193–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Andersen R, Norgaard P, Al-Jailawi MK, Svane IM. Late development of splenic sarcoidosis-like lesions in a patient with metastatic melanoma and long-lasting clinical response to ipilimumab. Oncoimmunology. 2014;3(8):e954506.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29(4):455–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. De Felice KM, Gupta A, Rakshit S, Khanna S, Kottschade LA, Finnes HD, et al. Ipilimumab-induced colitis in patients with metastatic melanoma. Melanoma Res. 2015;25(4):321–7.

    Article  PubMed  CAS  Google Scholar 

  85. • Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807–14. This pooled analysis of two major randomised trials demonstrated that efficacy outcomes are similar in patients who discontinued combination ipilimumab/nivolumab treatment because of AEs in the induction phase of treatment, and those who did not cease treatment.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, 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(5):611–22.

    Article  PubMed  CAS  Google Scholar 

  87. Carlino MS, Sandhu S. Safety and efficacy implications of discontinuing combination ipilimumab and nivolumab in advanced melanoma. J Clin Oncol. 2017;35(34):3792–3.

    Article  PubMed  Google Scholar 

  88. Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol. 2017;28(10):2377–85.

    Article  PubMed  CAS  Google Scholar 

  89. • Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer 2017;123(11):1904–11. This review aggregates and synthesizes the available preclinical and clinical data surrounding immune checkpoint inhibitor therapy in challenging clinical populations to assist oncologists in treatment decision making.

  90. • Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, ANM W, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncologia. 2017;28(2):368–76. This retrospective review of 119 patients with advanced melanoma and pre-existing autoimmune diseases and/or major irAEs to ipilimumab was the first to examine the safety and efficacy of anti-PD-1 agents in this population. Immune toxicities were relatively frequent but were often mild and easily managed without discontinuation of anti-PD-1. Response rates (33–40%) were quite high, suggesting that patients with a tendency to autoimmunity may benefit more from anti-PD-1 therapy.

    CAS  Google Scholar 

  91. Bowyer S, Prithviraj P, Lorigan P, Larkin J, McArthur G, Atkinson V, et al. Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. Br J Cancer. 2016;114(10):1084–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. • Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 2017. This study of 80 patients with metastatic melanoma who discontinued combination anti-CTLA-4/anti-PD-1 therapy due to clinically significant irAEs, was the first to evaluate the safety and efficacy of re-challenging such patients with anti-PD-1 monotherapy. Approximately 40% of patients experienced clinically significant recurrent or distinct toxicities with anti-PD-1 monotherapy, though these were generally low-grade and easily manageable. One patient did however die from SJS/TENS. Certain toxicities appeared more likely to recur than others.

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Authors and Affiliations

  1. Crown Princess Mary Cancer Centre, Westmead Hospital, Corner Hawkesbury & Darcy Roads, Westmead, NSW, 2145, Australia

    David J. Palmieri & Matteo S. Carlino

  2. Melanoma Institute of Australia, 40 Rocklands Road, Wollstonecraft, NSW, 2065, Australia

    Matteo S. Carlino

  3. University of Sydney, Camperdown, NSW, 2006, Australia

    Matteo S. Carlino

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  1. David J. Palmieri
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  2. Matteo S. Carlino
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Correspondence to Matteo S. Carlino.

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Matteo S. Carlino has received compensation from MSD, Bristol-Myers Squibb, Novartis, and Amgen for service on advisory boards.

David J. Palmieri declares that he has no conflict of interest.

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

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This article is part of the Topical Collection on Melanoma

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Palmieri, D.J., Carlino, M.S. Immune Checkpoint Inhibitor Toxicity. Curr Oncol Rep 20, 72 (2018). https://doi.org/10.1007/s11912-018-0718-6

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  • DOI: https://doi.org/10.1007/s11912-018-0718-6

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