Abstract
Due to the novelty of immune checkpoint inhibitors, their cutaneous adverse events (AEs) have only been recently characterized. This, along with the substantial rate of cutaneous reactions, has left many clinicians without sufficient familiarity to diagnose and treat cutaneous AEs. Pruritus and rash are among the top five immune-related AEs reported in clinical trials for this class of therapy. Incidence varies between 35 and 60% for cutaneous AEs among the seven FDA-approved drugs used as monotherapy or combination therapy. Although only 2% are reported as grade 3 or 4 events with monotherapy, the incidence can be as high as 6–9% for combination therapy and the impact on quality of life can be significant for these patients. Of ipilimumab patients, 43.5% have a cutaneous AE, and, at our institution, 20% of them had a dose interruption as a result. This means potentially 9% of patients have dose interruption of ipilimumab because of their cutaneous AEs. In the following chapter, we review the categories of these drugs, common cutaneous effects, their grading, and management options.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Naing, A., Hajjar, J., Gulley, J. L., Atkins, M. B., Ciliberto, G., Meric-Bernstam, F., & Hwu, P. (2020). Strategies for improving the management of immune-related adverse events. Journal for Immunotherapy of Cancer, 8(2), e001754.
Villadolid, J., & Amin, A. (2015). Immune checkpoint inhibitors in clinical practice: Update on management of immune-related toxicities. Translational Lung Cancer Research, 4(5), 560–575.
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al. (2019). Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. The New England Journal of Medicine, 381(16), 1535–1546.
Long, G. V., Atkinson, V., Cebon, J. S., et al. (2017). Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): An open-label, phase 1b trial. The Lancet Oncology, 18(9), 1202–1210.
Sanlorenzo, M., Vujic, I., Daud, A., et al. (2015). Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatology, 151(11), 1206–1212.
Teulings, H. E., Limpens, J., Jansen, S. N., et al. (2015). Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: A systematic review and meta-analysis. Journal of Clinical Oncology, 33(7), 773–781.
Attia, P., Phan, G. Q., Maker, A. V., et al. (2005). Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. Journal of Clinical Oncology, 23(25), 6043–6053.
Sundaresan, S., Nguyen, K. T., Nelson, K. C., Ivan, D., & Patel, A. B. (2017). Erythema multiforme major in a patient with metastatic melanoma treated with nivolumab. Dermatology Online Journal, 23(9).
Kubicki, S. L., Welborn, M. E., & Patel, A. B. (2018). Toxic epidermal necrolysis during co-therapy with ipilimumab and nivolumab. Journal of Immunotherapy and Precision Oncology, 1(2), 78–81.
Hodi, F. S., O’Day, S. J., McDermott, D. F., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. The New England Journal of Medicine, 363, 711–23.5.
Robert, C., Thomas, L., Bondarenko, I., et al. (2011). Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. The New England Journal of Medicine, 364, 2517–2526.
Robert, C., Ribas, A., Wolchok, J. D., et al. (2014). Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet, 384, 1109–17.7.
Robert, C., Long, G. V., Brady, B., et al. (2015). Nivolumab in previously untreated melanoma without BRAF mutation. The New England Journal of Medicine, 372, 320–330.
Weber, J. S., D’Angelo, S. P., Minor, D., et al. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate037): A randomised, controlled, open label, phase 3 trial. The Lancet Oncology, 16, 375–384.
Rizvi, N. A., Mazières, J., Planchard, D., et al. (2015). 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. The Lancet Oncology, 16, 257–265.
Garon, E. B., Rizvi, N. A., Hui, R., et al. (2015). Pembrolizumab for the treatment of non-small-cell lung cancer. The New England Journal of Medicine, 372, 2018–2028.
Di Giacomo, A. M., Biagioli, M., & Maio, M. (2010). The emerging toxicity profiles of anti-CTLA-4 anti-bodies across clinical indications. Seminars in Oncology, 37(5), 499–507.
Fujii, T., Colen, R. R., Bilen, M. A., et al. (2018). Incidence of immune-related adverse events and its association with treatment outcomes: The MD Anderson Cancer Center experience. Investigational New Drugs, 36(4), 638–646.
Horvat, T. Z., Adel, N. G., Dang TO, et al. (2015). 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. Journal of Clinical Oncology, 33(28), 3193–3198.
Coleman, E., Ko, C., Dai, F., Tomayko, M. M., Kluger, H., & Leventhal, J. S. (2019). Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. Journal of the American Academy of Dermatology, 80(4), 990–997.
Karri, P. V., Tahseen, D., & Patel, A. B. (2020). Treatment of checkpoint inhibitor-induced vitiligo in a patient with metastatic renal cell cancer. Dermatitis. Published online December 1.
Daxini, A., Cronin, K., & Sreih, A. G. (2018). Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clinical Rheumatology, 37(9), 2579–2584.
Cappelli, L. C., Shah, A. A., & Bingham, C. O. (2016). Cancer immunotherapy-induced rheumatic diseases emerge as new clinical entities. RMD Open, 2(2), e000321.
Messer, A., Drozd, B., Glitza, I. C., Lu, H., & Patel, A. B. (2020). Dermatomyositis associated with nivolumab therapy for melanoma: A case report and review of the literature. Dermatology Online Journal, 26(8).
Lacouture, M. E., Wolchok, J. D., Yosipovitch, G., Kähler, K. C., Busam, K. J., & Hauschild, A. (2014). Ipilimumab in patients with cancer and the management of dermatologic adverse events. Journal of the American Academy of Dermatology, 71(1), 161–169.
Nayar, N., Briscoe, K., & Fernandez, P. P. (2016). Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory meta-static melanoma. Journal of Immunotherapy, 39(3), 149–152.
Welborn, M., Kubicki, S. L., Garg, N., & Patel, A. B. (2020). Twelve cases of acneiform eruptions while on anti-CTLA4 therapy. Supportive Care in Cancer, 28(6), 2499–2502.
Kubicki, S. L., Welborn, M. E., Garg, N., Aung, P. P., & Patel, A. B. (2018). Granulomatous dermatitis associated with ipilimumab therapy (Ipilimumab associated granulomatous dermatitis). Journal of Cutaneous Pathology, 45(8), 636–638.
Welborn, M. E., Kubicki, S. L., & Patel, A. B. (2018). Pyoderma Gangrenosum following initiation of immune checkpoint inhibitor therapy. Journal of Immunotherapy and Precision Oncology, 1(2), 82–84.
Minkis, K., et al. (2013). The risk of rash associated with ipilimumab in patients with cancer: A systematic review of the literature and meta-analysis. Journal of the American Academy of Dermatology, 69(3), e121–e128.
Ohtsuka, M., Miura, T., Mori, T., Ishikawa, M., & Yamamoto, T. (2015). Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma. JAMA Dermatology, 151(7), 797–799.
Totonchy, M. B., Ezaldein, H. H., Ko, C. J., & Choi, J. N. (2016). Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatology, 152(5), 590–592.
Schaberg, K. B., Novoa, R. A., Wakelee, H. A., Kim, J., Cheung, C., Srinivas, S., & Kwong, B. Y. (2016). Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. Journal of Cutaneous Pathology, 43(4), 339–346.
Jour, G., Glitza, I. C., Ellis, R. M., et al. (2016). Autoimmune dermatologic toxicities from immune check point blockade with anti-PD-1 antibody therapy: A report on bullous skin eruptions. Journal of Cutaneous Pathology, 43(8), 688–696.
Naidoo, J., Schindler, K., Querfeld, C., et al. (2016). Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunology Research, 4(5), 383–389.
Freites-martinez, A., Kwong, B. Y., Rieger, K. E., Coit, D. G., Colevas, A. D., & Lacouture, M. E. (2017). Eruptive keratoacanthomas associated with pembrolizumab therapy. JAMA Dermatology, 153(7), 694–697.
Johnson, D., Patel, A. B., Uemura, M. I., et al. (2019). IL17A blockade successfully treated psoriasiform dermatologic toxicity from immunotherapy. Cancer Immunology Research, 7(6), 860–865.
Sowerby, L., Dewan, A. K., Granter, S., Gandhi, L., & Leboeuf, N. R. (2017). Rituximab treatment of nivolumab-induced bullous pemphigoid. JAMA Dermatology, 153(6), 603–605.
Lonowski, S., Sachsman, S., Patel, N., Truong, A., & Holland, V. (2020). Increasing evidence for omalizumab in the treatment of bullous pemphigoid. JAAD Case Reports, 6(3), 228–233.
Kaye, A., Gordon, S. C., Deverapalli, S. C., Her, M. J., & Rosmarin, D. (2018). Dupilumab for the treatment of recalcitrant bullous pemphigoid. JAMA Dermatology, 154(10), 1225–1226.
Bezinelli, L. M., Eduardo, F. P., Migliorati, C. A., et al. (2019). A severe, refractory case of mucous membrane pemphigoid after treatment with pembrolizumab: Brief communication. Journal of Immunotherapy, 42, 359–362.
Common Terminology Criteria for Adverse Events (CTCAE) v4.0. (2008). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 26 July 2016.
Brahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., et al. (2018). Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 36(17), 1714–1768. https://doi.org/10.1200/JCO.2017.77.6385
Hua, C., Boussemart, L., Mateus, C., et al. (2016). Association of vitiligo with tumor response in patients with meta-static melanoma treated with pembrolizumab. JAMA Dermatology, 152(1), 45–51.
Freeman-Keller, M., Kim, Y., Cronin, H., Richards, A., Gibney, G., & Weber, J. S. (2016). Nivolumab in resected and unresectable metastatic melanoma: Characteristics of immune-related adverse events and association with outcomes. Clinical Cancer Research, 22(4), 886–894.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Patel, A.B., Pacha, O. (2021). Skin Reactions to Immune Checkpoint Inhibitors. In: Naing, A., Hajjar, J. (eds) Immunotherapy. Advances in Experimental Medicine and Biology, vol 1342. Springer, Cham. https://doi.org/10.1007/978-3-030-79308-1_11
Download citation
DOI: https://doi.org/10.1007/978-3-030-79308-1_11
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-79307-4
Online ISBN: 978-3-030-79308-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)