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Cutaneous Adverse Events of Anti-PD-1 Therapy and BRAF Inhibitors

  • Skin Cancer (T Ito, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The treatment of advanced melanoma has undergone a dramatic transformation over the last decade with the advent of targeted and immunomodulatory therapies. This transition from cytotoxic chemotherapy has yielded improvements in both survival and quality of life; yet despite their therapeutic advantages, these treatments have been associated with a diverse range of cutaneous adverse events (AEs). These range from relatively benign eczematous conditions to more severe inflammatory and bullous disorders, and can include induction of second malignancies. AEs can result in serious morbidity and risk of mortality if not recognised and managed early. As a consequence of their novelty, and rapid uptake, these agents have been subject to intense scrutiny and there is a general understanding that cutaneous AEs should be anticipated in treatment plans. Dermatologists should be integrated into management teams to assist in the development of treatment protocols for anticipated common AEs and to provide expert management of more severe, rare or unusual AEs. Our experience has shown a reduction in treatment interruptions, more rapid recognition of unusual AEs and improved management pathways for patients suffering cutaneous AEs.

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References and Recommended Reading

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

  1. Mackiewicz J, Mackiewicz A. BRAF and MEK inhibitors in the era of immunotherapy in melanoma patients. Wspolczesna Onkol. 2017;2(1A):68–72.

    Google Scholar 

  2. Holmes A, Kern W, Martelli MP, Pucciarini A, et al. Mutations in hairy-cell leukemia. 2011;

  3. Czarniecka A, Oczko-Wojciechowska M, Barczyński M. BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence. Gland Surg. 2016;5(5):495–505.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Clarke CN, Kopetz ES. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointest Oncol. 2015;6(6):660–7.

    PubMed  PubMed Central  Google Scholar 

  5. Cui G, Liu D, Li W, Fu X, Liang Y, Li Y, et al. A meta-analysis of the association between BRAF mutation and nonsmall cell lung cancer. Med (United States). 2017;96(14).

  6. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF V600E and BRAF V600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32.

  7. Martin-Liberal J, Larkin J. Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Future Oncol. 2015;11(4):579–89.

    Article  CAS  PubMed  Google Scholar 

  8. Sanchez JN, Wang T, Cohen MS. BRAF and MEK inhibitors: use and resistance in BRAF-mutated cancers. Drugs. 2018;78(5):549–66. https://doi.org/10.1007/s40265-018-0884-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Koelblinger P, Thuerigen O, Dummer R. Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018;30(2):125–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pascale F, Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutated melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(2013):603–18 Available from: www.thelancet.com/oncology. Accessed 10 Sep 2019.

  11. Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314–22.

  12. Hwang SJE, Anforth R, Carlos G, Fernandez-Peñas P. Cutaneous adverse events of new anti-melanoma therapies: classification and management. Actas Dermosifiliogr. 2017;108(1):6–16.

    Article  CAS  PubMed  Google Scholar 

  13. Anforth R, Carlos G, Clements A, Kefford R, Fernandez-Peñas P. Cutaneous adverse events in patients treated with BRAF inhibitor-based therapies for metastatic melanoma for longer than 52 weeks. Br J Dermatol. 2015;172(1):239–43.

    Article  CAS  PubMed  Google Scholar 

  14. Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013;14(1):e11–8. https://doi.org/10.1016/S1470-2045(12)70413-8.

    Article  CAS  PubMed  Google Scholar 

  15. Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, Chou S, et al. Cutaneous toxic effects of BRAF inhibitors alone and in combination with MEK inhibitors for metastatic melanoma. JAMA Dermatol. 2015;151(10):1103–9.

    Article  PubMed  Google Scholar 

  16. Criscione VD, Weinstock MA, Naylor MF, Luque C, Eide MJ, Bingham SF. Actinic keratoses: natural history and risk of malignant transformation in the veterans affairs topical tretinoin chemoprevention trial. Cancer. 2009;115(11):2523–30.

    Article  PubMed  Google Scholar 

  17. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatologic Surg. 2007;33(9):1099–101.

    CAS  Google Scholar 

  18. Ali M, Anforth R, Senetiner F, Carlos G, Fernandez-Penas P. Mechanisms of BRAFi-induced hyperproliferative cutaneous conditions. Exp Dermatol. 2016;25(5):394–5.

    Article  PubMed  Google Scholar 

  19. Anforth R, Menzies A, Byth K, Carlos G, Chou S, Sharma R, et al. Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy. J Am Acad Dermatol. 2015;72(5):809–815.e1.

    Article  CAS  PubMed  Google Scholar 

  20. Takai T. Advances in histopathological diagnosis of keratoacanthoma. J Dermatol. 2017;44(3):304–14.

    Article  PubMed  Google Scholar 

  21. Chen P, Chen F, Zhou B. Systematic review and meta-analysis of prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma. Clin Exp Dermatol. 2019;44(3):243–51.

    Article  CAS  PubMed  Google Scholar 

  22. Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of targeted therapies: part II: inhibitors of intracellular molecular signaling pathways. J Am Acad Dermatol. 2015;72(2):221–36.

    Article  CAS  PubMed  Google Scholar 

  23. Herms F, Kramkimel N, Regnier-Rosencher E, Carlotti A, Chanal J, Boitier F, et al. Age and clear eyes are associated with an increased risk of cutaneous squamous cell carcinomas in vemurafenib-treated melanoma patients. Melanoma Res. 2016;26(5):487–91.

    Article  CAS  PubMed  Google Scholar 

  24. Anforth RM, Blumetti TCMP, Kefford RF, Sharma R, Scolyer RA, Kossard S, et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol. 2012;167(5):1153–60.

  25. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65. https://doi.org/10.1016/S0140-6736(12)60868-X.

    Article  CAS  PubMed  Google Scholar 

  26. Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol. 2013;27(1):11–8.

    Article  CAS  PubMed  Google Scholar 

  27. Vemurafenib E. Ultraviolet A and Photosensitivity during vemurafenib therapy Staphylococcus aureus reactivation osteomyelitis after 75 years. 2012;480–1.

  28. Woods JA, Ferguson JS, Kalra S, Degabriele A, Gardner J, Logan P, et al. The phototoxicity of vemurafenib: an investigation of clinical monochromator phototesting and in vitro phototoxicity testing. J Photochem Photobiol B Biol. 2015;151:233–8. https://doi.org/10.1016/j.jphotobiol.2015.08.004.

    Article  CAS  Google Scholar 

  29. Wang SQ, Xu H, Stanfield JW, Osterwalder U, Herzog B. Comparison of ultraviolet a light protection standards in the United States and European Union through in vitro measurements of commercially available sunscreens. J Am Acad Dermatol. 2017;77(1):42–7. https://doi.org/10.1016/j.jaad.2017.01.017.

    Article  CAS  PubMed  Google Scholar 

  30. Mudaliar K, Tetzlaff MT, Duvic M, Ciurea A, Hymes S, Milton DR, et al. BRAF inhibitor therapy-associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression. Hum Pathol. 2016;50:79–89. https://doi.org/10.1016/j.humpath.2015.12.003.

    Article  CAS  PubMed  Google Scholar 

  31. Mochel MC, Hammond MR, Frederick DT, Alora-Palli MB, Piris A, Flaherty KT, et al. Melanocytic nevi excised during B-Raf proto-oncogene (BRAF) inhibitor therapy: a study of 19 lesions from 10 patients presented in part at the American Society of Dermatopathology 51st Annual Meeting, Chicago, IL, November 2014. J Am Acad Dermatol. 2015;73(3):491–499.e2. https://doi.org/10.1016/j.jaad.2015.06.006.

    Article  CAS  PubMed  Google Scholar 

  32. Parekh V, Sobanko J, Miller CJ, Karakousis G, Xu W, Letrero R, et al. NRAS Q61R and BRAF G466A mutations in atypical melanocytic lesions newly arising in advanced melanoma patients treated with vemurafenib. J Cutan Pathol. 2019;46(3):190–4.

  33. Sinha R, Larkin J, Gore M, Fearfield L. Cutaneous toxicities associated with vemurafenib therapy in 107 patients with BRAF V600E mutation-positive metastatic melanoma, including recognition and management of rare presentations. Br J Dermatol. 2015;173(4):1024–31.

    Article  CAS  PubMed  Google Scholar 

  34. Pattanaprichakul P, Tetzlaff MT, Lapolla WJ, Torres-Cabala CA, Duvic M, Prieto VG, et al. Sweet syndrome following vemurafenib therapy for recurrent cholangiocarcinoma. J Cutan Pathol. 2014;41(3):326–8.

  35. Yorio JT, Mays SR, Ciurea AM, Cohen PR, Wang WL, Hwu WJ, et al. Case of vemurafenib-induced Sweet’s syndrome. J Dermatol. 2014;41(9):817–20.

  36. Peuvrel L, Quéreux G, Saint-Jean M, Brocard A, Nguyen JM, Khammari A, et al. Profile of vemurafenib-induced severe skin toxicities. J Eur Acad Dermatol Venereol. 2016;30(2):250–7.

    Article  CAS  PubMed  Google Scholar 

  37. Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys. 2016;95(2):632–46. https://doi.org/10.1016/j.ijrobp.2016.01.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bellón T, Lerma V, González-Valle O, González Herrada C, De Abajo FJ. Vemurafenib-induced toxic epidermal necrolysis: possible cross-reactivity with other sulfonamide compounds. Br J Dermatol. 2016;174(3):621–4.

    Article  PubMed  CAS  Google Scholar 

  39. Sinha R, Lecamwasam K, Purshouse K, Reed J, Middleton MR, Fearfield L. Toxic epidermal necrolysis in a patient receiving vemurafenib for treatment of metastatic malignant melanoma. Br J Dermatol. 2014;170(4):997–9.

    Article  CAS  PubMed  Google Scholar 

  40. Jeudy G, Dalac-Rat S, Bonniaud B, Hervieu A, Petrella T, Collet E, et al. Successful switch to dabrafenib after vemurafenib-induced toxic epidermal necrolysis. Br J Dermatol. 2015;172(5):1454–5.

  41. Henning B, Stieger P, Kamarachev J, Dummer R, Goldinger SM. Pyogenic granuloma in patients treated with selective BRAF inhibitors: another manifestation of paradoxical pathway activation. Melanoma Res. 2016;26(3):304–7.

    Article  CAS  PubMed  Google Scholar 

  42. Hui Ong EL, Sinha R, Jmor S, Fearfield L. BRAF inhibitor-associated granulomatous dermatitis: a report of 3 cases. Am J Dermatopathol. 2019;41(3):214–7.

    Article  PubMed  Google Scholar 

  43. Garrido MC, Gutierrez C, Riveiro-Falkenbach E, Ortiz P, Rodriguez-Peralto JL. BRAF inhibitor-induced antitumoral granulomatous dermatitis eruption in advanced melanoma. Am J Dermatopathol. 2015;37(10):795–8.

  44. Hern I, Gregorio U, Su R. Persistent granulomatous cutaneous drug eruption to a BRAF inhibitor. J Am Acad Dermatol. 2017;76(6):AB195.

    Google Scholar 

  45. Jiang B, Patino MM, Gross AJ, Leong SPL, Moretto JC, Kashani-Sabet M, et al. Diffuse granulomatous panniculitis associated with anti PD-1 antibody therapy. JAAD Case Rep. 2018;4(1):13–6.

  46. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992.

  47. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009.

  48. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007.

  49. Gandini S, Massi D, Mandala M. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2016;100:88–98.

    Article  PubMed  Google Scholar 

  50. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015.

  51. Amos SM, Duong CPM, Westwood JA, Ritchie DS, Junghans RP, Darcy PK, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011.

  52. Alatrash G, Jakher H, Stafford PD, Mittendorf EA. Cancer immunotherapies, their safety and toxicity. Expert Opin Drug Saf. 2013.

  53. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clin Oncol. 2015.

  54. Tsai KK, Zarzoso I, Daud AI. PD-1 and PD-L1 antibodies for melanoma. Hum Vaccin Immunother. 2014;10(11):3111–6.

    Article  PubMed  Google Scholar 

  55. Markham A, Duggan S. Cemiplimab: first global approval. Drugs. 2018;78(17):1841–6.

    Article  CAS  PubMed  Google Scholar 

  56. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015.

  57. •• Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017; Comment - A thorough review of the literature that is reasonably recent and contains the overwhilming bulk of AEs reported to date.

  58. • 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; Comment: An excellent and still recent review, the only in the literature to provide calculated relative risk and incidence statistics.

  59. Baroudjian B, Arangalage D, Cuzzubbo S, Hervier B, Lebbé C, Lorillon G, et al. Management of immune-related adverse events resulting from immune checkpoint blockade. Expert Rev Anticancer Ther. 2019;19(3):209–22.

    Article  CAS  PubMed  Google Scholar 

  60. 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. 2015;26(12):2375–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, 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. 2014.

  62. Hwang SJE, 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.

  63. •• Chan L, SJE H, Kyaw M, Byth K, Carlino MS, Chou S, et al. The oncological survival and prognosis of individuals receiving PD-1 inhibitor with and without immunologic cutaneous adverse events. J Am Acad Dermatol. 2019; Comment: Recently published work associating any cutaneous AE with improved progression free and overall survival. This is important as benefit had only been previously demonstrated in two earlier studies, and was specific to the development of vitiligo-like depigmentation rather than cutaneous AEs in general.

  64. Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015.

  65. Zhao CY, Hwang SJE, Anforth R, Carlos G, Chou S, Carlino M, et al. Incidence of basal cell carcinoma and squamous cell carcinoma in patients on antiprogrammed cell death-1 therapy for metastatic melanoma. J Immunother. 2018;41(7):343–9.

  66. Hwang SJE, Wakade D, Byth K, Chou S, Turner L, Gurney H, et al. Skin toxicities of anti-programmed death (anti-PD-1) antibodies in patients with advanced solid organ tumors. Press. 2019.

  67. George S, Motzer RJ, Hammers HJ, Redman BG, Kuzel TM, Tykodi SS, et al. Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016.

  68. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014.

  69. Lo JA, Fisher DE, Flaherty KT. Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy. JAMA Oncol. 2015.

  70. Wolner ZJ, Marghoob AA, Pulitzer MP, Postow MA, Marchetti MA. A case report of disappearing pigmented skin lesions associated with pembrolizumab treatment for metastatic melanoma. Br J Dermatol. 2018;178(1):265–9.

    Article  CAS  PubMed  Google Scholar 

  71. Zhao CY, Hwang SJE, Wakade D, Carlos G, Anforth R, Fernández-Peñas P. Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: an observational study. Australas J Dermatol. 2017;58(4):292–8.

    Article  PubMed  Google Scholar 

  72. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016.

  73. 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.

  74. 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.

  75. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013.

  76. 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.

  77. Sullivan RJ, Flaherty KT. Pembrolizumab for treatment of patients with advanced or unresectable melanoma. Clin Cancer Res. 2015.

  78. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.

  79. Jour G, Glitza IC, Ellis RM, Torres-Cabala CA, Tetzlaff MT, Li JY, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016.

  80. Schaberg KB, Novoa RA, Wakelee HA, Kim J, Cheung C, Srinivas S, et al. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol. 2016.

  81. Joseph RW, Cappel M, Goedjen B, Gordon M, Kirsch B, Gilstrap C, et al. Lichenoid dermatitis in three patients with metastatic melanoma treated with anti–PD-1 therapy. Cancer Immunol Res. 2015;3(1):18–22.

    Article  PubMed  Google Scholar 

  82. 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.

  83. Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP, Girardi M, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti–programmed cell death 1 and anti–programmed cell death ligand 1 immunotherapy. JAMA Dermatol. 2016;152(10):1128–36.

  84. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016.

  85. Totonchy MB, Ezaldein HH, Ko CJ, Choi JN. Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatol. 2016.

  86. Ohtsuka M, Miura T, Mori T, Ishikawa M, Yamamoto T. Occurrence of psoriasiform eruption during nivolumab therapy for primary oral mucosal melanoma. JAMA Dermatol. 2015.

  87. Bonigen J, Raynaud-Donzel C, Hureaux J, Kramkimel N, Blom A, Jeudy G, et al. Anti-PD1-induced psoriasis: a study of 21 patients. J Eur Acad Dermatol Venereol. 2017.

  88. Kato Y, Otsuka A, Miyachi Y, Kabashima K. Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol. 2016.

  89. Matsumura N, Ohtsuka M, Kikuchi N, Yamamoto T. Exacerbation of psoriasis during nivolumab therapy for metastatic melanoma. Acta Derm Venereol. 2016.

  90. Sahuquillo-Torralba A, Ballester-Sánchez R, Pujol-Marco C, Botella-Estrada R. Pembrolizumab: a new drug that can induce exacerbations of psoriasis. Actas Dermosifiliogr. 2016.

  91. Star P, Cheung K, Long G, Brown P, Smith A, Guitera P, et al. Immunotherapy-induced pustular psoriasis in a patient with metastatic melanoma. Australas J Dermatol. 2017.

  92. Hwang SJE, 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.

  93. Carlos G, Anforth R, Chou S, Clements A, Fernandez-Peñas P. A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. Melanoma Res. 2015;

  94. Mochel MC, Ming ME, Imadojemu S, Gangadhar TC, Schuchter LM, Elenitsas R, et al. Cutaneous autoimmune effects in the setting of therapeutic immune checkpoint inhibition for metastatic melanoma. J Cutan Pathol. 2016.

  95. Adachi E, Honda T, Nonoyama S, Irie H, Yamamura K, Otsuka A, et al. Severe bullous pemphigoid in a metastatic lung cancer patient treated with pembrolizumab. J Dermatol. 2019.

  96. Damsky W, Kole L, Tomayko MM. Development of bullous pemphigoid during nivolumab therapy. JAAD Case Rep. 2016.

  97. Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham J, Page DB, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016.

  98. Wakade DV, Carlos G, Hwang SJE, Chou S, Hui R, Fernandez-Peñas P. PD-1 inhibitors induced bullous lichen planus-like reactions: a rare presentation and report of three cases. Melanoma Res. 2016;26(4):421–4.

    Article  PubMed  Google Scholar 

  99. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014.

  100. Thibult ML, Mamessier E, Gertner-dardenne J, Pastor S, Just-landi S, Xerri L, et al. Pd-1 is a novel regulator of human B-cell activation. Int Immunol. 2013.

  101. Sibaud V, David I, Lamant L, Resseguier S, Radut R, Attal J, et al. Acute skin reaction suggestive of pembrolizumab-induced radiosensitization. Melanoma Res. 2015.

  102. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015.

  103. de Golian E, Kwong BY, Swetter SM, Pugliese SB. Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol. 2016;17(11). https://doi.org/10.1007/s11864-016-0434-0.

  104. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015.

  105. Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, et al. Phase i study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015.

  106. Cotliar J, Raja N, Raz D, Boswell WJ, Chen R, Querfeld C. Pembrolizumab-associated sarcoidosis. JAAD Case Rep. 2016.

  107. 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.

  108. Danlos F-X, Pagès C, Baroudjian B, Vercellino L, Battistella M, Mimoun M, et al. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest. 2016;149(5):e133–6.

  109. Mobini N, Dhillon R, Dickey J, Spoon J, Sadrolashrafi K. Exclusive cutaneous and subcutaneous sarcoidal granulomatous inflammation due to immune checkpoint inhibitors: report of two cases with unusual manifestations and review of the literature. Case Rep Dermatol Med. 2019;2019.

  110. Ogawa T, Ishitsuka Y, Iwamoto K, Koguchi-Yoshioka H, Tanaka R, Watanabe R, et al. Programmed cell death 1 blockade-induced cutaneous sarcoid-like epithelioid granulomas in advanced melanoma: a case report. J Eur Acad DermatolVenereol. 2018;32(7):e260–1.

    Article  CAS  Google Scholar 

  111. Birnbaum MR, Ma MW, Fleisig S, Packer S, Amin BD, Jacobson M, et al. Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma. JAAD Case Rep. 2017;3(3):208–11.

  112. Dimitriou F, Frauchiger AL, Urosevic-Maiwald M, Naegeli MC, Goldinger SM, Barysch M, et al. Sarcoid-like reactions in patients receiving modern melanoma treatment. Melanoma Res. 2018;28(3):230–6.

  113. Suozzi KC, Stahl M, Ko CJ, Chiang A, Gettinger SN, Siegel MD, et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2016;2(3):264–8.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, Korivi BR, Landon GA, Nagarajan P, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy—report of 2 patients. J Cutan Pathol. 2017;44(12):1080–6.

  115. Beutler BD, Cohen PR. Sarcoidosis in melanoma patients: case report and literature review. Cancers (Basel). 2015;7(2):1005–21.

    Article  CAS  Google Scholar 

  116. Broos CE, Koth LL, van Nimwegen M, Paulissen SMJ, van Hamburg JP, Annema JT, et al. Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes. Eur Respir J. 2018;51(3):1701124.

    Article  PubMed  CAS  Google Scholar 

  117. Goldinger SM, Stieger P, Meier B, Micaletto S, Contassot E, French LE, et al. Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res. 2016;22(16):4023–9.

  118. Nayar N, Briscoe K, Penas PF. Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma. J Immunother. 2016.

  119. Haddad N, Vidal-Trecan T, Baroudjian B, Zagdanski A-M, Arangalage D, Battistella M, et al. Acquired generalized lipodystrophy under immune checkpoint inhibition. Br J Dermatol. 2019.

  120. Jehl A, Cugnet-Anceau C, Vigouroux C, Legeay AL, Dalle S, Harou O, et al. Acquired generalized lipodystrophy: a new cause of anti-PD-1 immune-related diabetes. Diabetes Care. 2019;42(10):2008–10.

  121. Falcao CK, Cabral MCS, Mota JM, Arbache ST, Costa-Riquetto AD, Muniz DQB, et al. Acquired lipodystrophy associated with nivolumab in a patient with advanced renal cell carcinoma. J Clin Endocrinol Metab. 2019.

  122. Gnanendran S, Miller J, Jain S, Archer C, Peters G, Hwang SJE. Acquired lipodystrophy associated with immune check point inhibitors. Press. 2019;

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Authors and Affiliations

  1. Dermatology Department, The Canberra Hospital, Australian National University, Level 2, Building 6, Canberra, Australian Capital Territory, Australia

    Subashini Sharon Gnanendran MBBS, Shelley Ji Eun Hwang MBBS (Hons), MMed (Clin Epi) & Andrew Charles Miller MBBS, BSC (Med), FACD

  2. ANU Medical School, Australian National University, Acton, Canberra, ACT, 2600, Australia

    Subashini Sharon Gnanendran MBBS, Lauren Maree Turner BSci (Hons), PhD, MChD, James Austin Miller BPhty (Hons), MMsk, Sports Phty & Andrew Charles Miller MBBS, BSC (Med), FACD

  3. Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia

    Shelley Ji Eun Hwang MBBS (Hons), MMed (Clin Epi)

  4. ACT Dermatology, 6/5 McKay Gardens, Turner, ACT, 2612, Australia

    Andrew Charles Miller MBBS, BSC (Med), FACD

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  1. Subashini Sharon Gnanendran MBBS
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  2. Lauren Maree Turner BSci (Hons), PhD, MChD
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Correspondence to James Austin Miller BPhty (Hons), MMsk, Sports Phty.

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Subashini Sharon Gnanendran declares that she has no conflict of interest.

Lauren Maree Turner declares that she has no conflict of interest.

James Austin Miller declares that he has no conflict of interest.

Shelley Ji Eun Hwang declares that she has no conflict of interest.

Andrew Charles Miller declares that he has no conflict of interest.

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Subashini Sharon Gnanendran and Lauren Maree Turner are joint first authors

This article is part of the Topical Collection on Skin Cancer

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Gnanendran, S.S., Turner, L.M., Miller, J.A. et al. Cutaneous Adverse Events of Anti-PD-1 Therapy and BRAF Inhibitors. Curr. Treat. Options in Oncol. 21, 29 (2020). https://doi.org/10.1007/s11864-020-0721-7

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