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Dermatological Complications of Systemic Therapies for Melanoma

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Cutaneous Melanoma

Abstract

Modern melanoma therapies, such as targeted therapy (TT) and immunotherapy (IT), proved to significantly prolong progression free and overall survival in patients with advanced melanoma. Since their approval for metastatic disease, these drugs have also been tested and met with success in the adjuvant setting. As the list of indications for systemic melanoma therapies expands, increasing numbers of patients are exposed to systemic therapies and placed at risk of developing adverse events.

The skin is the organ that is most commonly affected by modern melanoma therapies. Cutaneous adverse events occur in over 95% of patients treated with BRAF inhibitors, over 90% of those treated with MEK inhibitors, and less frequently in patients undergoing combination therapy. With immune checkpoint-based immunotherapy the incidence rates vary between 43.5% and 58.7% with anti-CTLA-4 antibodies, 37.4–41.9% in those receiving anti-PD-1, and up to 70% in those receiving combination immunotherapy.

As dermatologic adverse events can cause significant morbidity, patient education, prophylaxis, timely recognition, and early intervention of adverse events are crucial in management of patients receiving modern systemic therapies.

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References

  • Anforth RM, Blumetti TCMP, Kefford RF, Sharma R, Scolyer RA, Kossard S, Long GV, Fernandez-Peñas P (2012) Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 167:1153. https://doi.org/10.1111/j.1365-2133.2012.11155.x

    Article  CAS  PubMed  Google Scholar 

  • Anforth R, Blumetti TCMP, Clements A, Kefford R, Long GV, Fernandez-Peñas P (2013a) Systemic retinoids for the chemoprevention of cutaneous squamous cell carcinoma and verrucal keratosis in a cohort of patients on BRAF inhibitors. Br J Dermatol 169:1310–1313. https://doi.org/10.1111/bjd.12519

    Article  CAS  PubMed  Google Scholar 

  • Anforth R, Fernandez-Peñas P, Long GV (2013b) Cutaneous toxicities of RAF inhibitors. Lancet Oncol 14:e11–e18. https://doi.org/10.1016/S1470-2045(12)70413-8

    Article  CAS  PubMed  Google Scholar 

  • Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, Jäger D, Pietanza MC, Le DT, de Braud F, Morse MA, Ascierto PA, Horn L, Amin A, Pillai RN, Evans J, Chau I, Bono P, Atmaca A, Sharma P, Harbison CT, Lin C-S, Christensen O, Calvo E (2016) Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17:883–895. https://doi.org/10.1016/S1470-2045(16)30098-5

    Article  CAS  PubMed  Google Scholar 

  • Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, Guckert M, Schadendorf D, Kefford RF, Grob J-J, Hamid O, Amaravadi R, Simeone E, Wilhelm T, Kim KB, Long GV, Martin A-M, Mazumdar J, Goodman VL, Trefzer U (2013) Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 31:3205–3211. https://doi.org/10.1200/JCO.2013.49.8691

    Article  CAS  PubMed  Google Scholar 

  • Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J (2016) Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248–1260. https://doi.org/10.1016/S1470-2045(16)30122-X

    Article  CAS  PubMed  Google Scholar 

  • Assi H, Wilson KS (2013) Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. Curr Oncol Toronto 20:e165–e169. https://doi.org/10.3747/co.20.1265

    Article  CAS  Google Scholar 

  • Balagula Y, Barth Huston K, Busam KJ, Lacouture ME, Chapman PB, Myskowski PL (2011) Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Investig New Drugs 29:1114–1121. https://doi.org/10.1007/s10637-010-9567-3

    Article  CAS  Google Scholar 

  • Banerji U, Camidge DR, Verheul HMW, Agarwal R, Sarker D, Kaye SB, Desar IME, Timmer-Bonte JNH, Eckhardt SG, Lewis KD, Brown KH, Cantarini MV, Morris C, George SMA, Smith PD, van Herpen CML (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16:1613–1623. https://doi.org/10.1158/1078-0432.CCR-09-2483

    Article  CAS  PubMed  Google Scholar 

  • Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D (2018) Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 360:k793

    Article  Google Scholar 

  • Belum VR, Fontanilla Patel H, Lacouture ME, Rodeck U (2013) Skin toxicity of targeted cancer agents: mechanisms and intervention. Future Oncol London 9:1161–1170. https://doi.org/10.2217/fon.13.62

    Article  CAS  Google Scholar 

  • Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, Motzer RJ, Wu S, Busam KJ, Wolchok JD, Lacouture ME (2016) Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer Oxford 1990(60):12–25. https://doi.org/10.1016/j.ejca.2016.02.010

    Article  CAS  Google Scholar 

  • Blank CU, Enk A (2015) Therapeutic use of anti-CTLA-4 antibodies. Int Immunol 27:3–10. https://doi.org/10.1093/intimm/dxu076

    Article  CAS  PubMed  Google Scholar 

  • Boniface K, Dutriaux C, Prey S, Taieb A, Seneschal J (2018) Vitiligo-like lesions in patients receiving anti-programmed cell death-1 therapies are distinct from spontaneously occurring active vitiligo. J Am Acad Dermatol 78:e17–e18. https://doi.org/10.1016/j.jaad.2017.08.028

    Article  PubMed  Google Scholar 

  • Boussemart L, Routier E, Mateus C, Opletalova K, Sebille G, Kamsu-Kom N, Thomas M, Vagner S, Favre M, Tomasic G, Wechsler J, Lacroix L, Robert C (2013) Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 24:1691–1697. https://doi.org/10.1093/annonc/mdt015

    Article  CAS  PubMed  Google Scholar 

  • Boussemart L, Girault I, Malka-Mahieu H, Mateus C, Routier E, Rubington M, Kamsu-Kom N, Thomas M, Tomasic G, Agoussi S, Breckler M, Laporte M, Lacroix L, Eggermont AM, Cavalcanti A, Grange F, Adam J, Vagner S, Robert C (2016) Secondary tumors arising in patients undergoing BRAF inhibitor therapy exhibit increased BRAF-CRAF heterodimerization. Cancer Res 76:1476–1484. https://doi.org/10.1158/0008-5472.CAN-15-2900-T

    Article  CAS  PubMed  Google Scholar 

  • Cancer Genome Atlas (2015) Genomic Classification of Cutaneous Melanoma. Network Cell 161(7):1681–96. https://doi.org/10.1016/j.cell.2015.05.044

    Article  Google Scholar 

  • Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, Chou S, Fernandez-Peñas P (2015) Cutaneous toxic effects of BRAF inhibitors alone and in combination with MEK inhibitors for metastatic melanoma. JAMA Dermatol 151:1103–1109. https://doi.org/10.1001/jamadermatol.2015.1745

    Article  PubMed  Google Scholar 

  • Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AMM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. https://doi.org/10.1056/NEJMoa1103782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins LK, Chapman MS, Carter JB, Samie FH (2017) Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer 41:125–128. https://doi.org/10.1016/j.currproblcancer.2016.12.001

    Article  PubMed  Google Scholar 

  • de Golian E, Kwong BY, Swetter SM, Pugliese SB (2016) Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol 17:57. https://doi.org/10.1007/s11864-016-0434-0

    Article  PubMed  Google Scholar 

  • Dika E, Ravaioli GM, Fanti PA, Piraccini BM, Lambertini M, Chessa MA, Baraldi C, Ribero S, Andrea A, Melotti B, Patrizi A (2017) Cutaneous adverse effects during ipilimumab treatment for metastatic melanoma: a prospective study. Eur J Dermatol 27:266–270. https://doi.org/10.1684/ejd.2017.3023

    Article  CAS  PubMed  Google Scholar 

  • Dimitriou F, Frauchiger AL, Urosevic-Maiwald M, Naegeli MC, Goldinger SM, Barysch M, Franzen D, Kamarachev J, Braun R, Dummer R, Mangana J (2018) Sarcoid-like reactions in patients receiving modern melanoma treatment. Melanoma Res 28:230–236. https://doi.org/10.1097/CMR.0000000000000437

    Article  PubMed  PubMed Central  Google Scholar 

  • Dummer R, Rinderknecht J, Goldinger SM (2012) Ultraviolet A and photosensitivity during vemurafenib therapy. N Engl J Med 366:480–481. https://doi.org/10.1056/NEJMc1113752

    Article  CAS  PubMed  Google Scholar 

  • Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT (2018) Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19:603–615. https://doi.org/10.1016/S1470-2045(18)30142-6

    Article  CAS  PubMed  Google Scholar 

  • Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob J-J, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C (2018) Adjuvant Pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801. https://doi.org/10.1056/NEJMoa1802357

    Article  CAS  PubMed  Google Scholar 

  • Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, Pavlick AC, O’Day SJ, Blackman SC, Curtis CM, Lebowitz P, Ma B, Ouellet D, Kefford RF (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379:1893–1901. https://doi.org/10.1016/S0140-6736(12)60398-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22:886–894. https://doi.org/10.1158/1078-0432.CCR-15-1136

    Article  CAS  PubMed  Google Scholar 

  • Gabeff R, Dutartre H, Khammari A, Boisrobert A, Nguyen J-M, Quereux G, Brocard A, Saint-Jean M, Peuvrel L, Dreno B (2015) Phototoxicity of B-RAF inhibitors: exclusively due to UVA radiation and rapidly regressive. Eur J Dermatol 25:452–456. https://doi.org/10.1684/ejd.2015.2628

    Article  CAS  PubMed  Google Scholar 

  • Gelot P, Dutartre H, Khammari A, Boisrobert A, Schmitt C, Deybach J-C, Nguyen J-M, Seité S, Dréno B (2013) Vemurafenib: an unusual UVA-induced photosensitivity. Exp Dermatol 22:297–298. https://doi.org/10.1111/exd.12119

    Article  CAS  PubMed  Google Scholar 

  • Goldinger SM, Stieger P, Meier B, Micaletto S, Contassot E, French LE, Dummer R (2016) Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res 22:4023–4029. https://doi.org/10.1158/1078-0432.CCR-15-2872

    Article  CAS  PubMed  Google Scholar 

  • Griffin LL, Cove-Smith L, Alachkar H, Radford JA, Brooke R, Linton KM (2018) Toxic epidermal necrolysis (TEN) associated with the use of nivolumab (PD-1 inhibitor) for lymphoma. JAAD Case Rep 4:229–231. https://doi.org/10.1016/j.jdcr.2017.09.028

    Article  PubMed  PubMed Central  Google Scholar 

  • Hamid O, Robert C, Daud A, Hodi FS, Hwu W-J, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (Anti-PD-1) in melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1305133

    Article  CAS  Google Scholar 

  • Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, Voss MH, Sharma P, Pal SK, Razak ARA, Kollmannsberger C, Heng DYC, Spratlin J, McHenry MB, Amin A (2017) Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 Study. J Clin Oncol 35:3851–3858. https://doi.org/10.1200/JCO.2016.72.1985

    Article  CAS  PubMed  Google Scholar 

  • Hassel JC, Heinzerling L, Aberle J, Bähr O, Eigentler TK, Grimm M-O, Grünwald V, Leipe J, Reinmuth N, Tietze JK, Trojan J, Zimmer L, Gutzmer R (2017) Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat Rev 57:36–49. https://doi.org/10.1016/j.ctrv.2017.05.003

    Article  CAS  PubMed  Google Scholar 

  • Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJC, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431–435. https://doi.org/10.1038/nature08833

    Article  CAS  PubMed  Google Scholar 

  • Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin A-M, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365. https://doi.org/10.1016/S0140-6736(12)60868-X

    Article  CAS  PubMed  Google Scholar 

  • Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X, Antonia SJ (2017) 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 18:31–41. https://doi.org/10.1016/S1470-2045(16)30624-6

    Article  CAS  PubMed  Google Scholar 

  • Hellmann MD, Ciuleanu T-E, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O’Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104. https://doi.org/10.1056/NEJMoa1801946

    Article  CAS  PubMed  Google Scholar 

  • Hodi FS, Oble DA, Drappatz J, Velazquez EF, Ramaiya N, Ramakrishna N, Day AL, Kruse A, Mac Rae S, Hoos A, Mihm M (2008) CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS. Nat Clin Pract Oncol 5:557–561. https://doi.org/10.1038/ncponc1183

    Article  CAS  PubMed  Google Scholar 

  • Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJM, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor DR, Salama AK, Taylor MH, Ott PA, Horak C, Gagnier P, Jiang J, Wolchok JD, Postow MA (2016) 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. https://doi.org/10.1016/S1470-2045(16)30366-7

    Article  CAS  Google Scholar 

  • Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, Viollet R, Thomas M, Roy S, Benannoune N, Tomasic G, Soria J-C, Champiat S, Texier M, Lanoy E, Robert C (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:45–51. https://doi.org/10.1001/jamadermatol.2015.2707

    Article  PubMed  Google Scholar 

  • Ito J, Fujimoto D, Nakamura A, Nagano T, Uehara K, Imai Y, Tomii K (2017) Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer Amsterdam 109:58–61. https://doi.org/10.1016/j.lungcan.2017.04.020

    Article  Google Scholar 

  • Jaber SH, Cowen EW, Haworth LR, Booher SL, Berman DM, Rosenberg SA, Hwang ST (2006) Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol 142:166–172. https://doi.org/10.1001/archderm.142.2.166

    Article  CAS  PubMed  Google Scholar 

  • Kato Y, Otsuka A, Miyachi Y, Kabashima K (2016) Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol 30:e89–e91. https://doi.org/10.1111/jdv.13336

    Article  CAS  PubMed  Google Scholar 

  • Khavari TA, Rinn J (2007) Ras/Erk MAPK signaling in epidermal homeostasis and neoplasia. Cell Cycle Georget 6:2928–2931. https://doi.org/10.4161/cc.6.23.4998

    Article  CAS  Google Scholar 

  • Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD (2013) Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 31:482–489. https://doi.org/10.1200/JCO.2012.43.5966

    Article  CAS  PubMed  Google Scholar 

  • Kirchberger MC, Ugurel S, Mangana J, Heppt MV, Eigentler TK, Berking C, Schadendorf D, Schuler G, Dummer R, Heinzerling L (2018) MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: results of a retrospective multicentre analysis of 364 patients. Eur J Cancer 1990(98):10–16. https://doi.org/10.1016/j.ejca.2018.04.010

    Article  CAS  Google Scholar 

  • Kuwatsuka Y, Iwanaga A, Kuwatsuka S, Okubo Y, Murayama N, Ishii N, Hashimoto T, Utani A (2018) Bullous pemphigoid induced by ipilimumab in a patient with metastatic malignant melanoma after unsuccessful treatment with nivolumab. J Dermatol 45:e21–e22. https://doi.org/10.1111/1346-8138.14043

    Article  PubMed  Google Scholar 

  • Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, Kim CC, McCormack CJ, Myskowski PL, Spleiss O, Trunzer K, Su F, Nelson B, Nolop KB, Grippo JF, Lee RJ, Klimek MJ, Troy JL, Joe AK (2013) Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. https://doi.org/10.1634/theoncologist.2012-0333

    Article  CAS  Google Scholar 

  • Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A (2014) Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 71:161–169. https://doi.org/10.1016/j.jaad.2014.02.035

    Article  CAS  PubMed  Google Scholar 

  • Larkin J, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:1270–1271. https://doi.org/10.1056/NEJMc1509660

    Article  PubMed  Google Scholar 

  • Lomax AJ, Lim J, Cheng R, Sweeting A, Lowe P, McGill N, Shackel N, Chua EL, McNeil C (2018) Immune toxicity with checkpoint inhibition for metastatic melanoma: case series and clinical management. J Skin Cancer 2018:9602540. https://doi.org/10.1155/2018/9602540

    Article  PubMed  PubMed Central  Google Scholar 

  • Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, Hill AG, Ribas A, Atkins MB, Thompson JA, Hwu W-J, Hodi FS, Menzies AM, Guminski AD, Kefford R, Kong BY, Tamjid B, Srivastava A, Lomax AJ, Islam M, Shu X, Ebbinghaus S, Ibrahim N, Carlino MS (2017) Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 18:1202–1210. https://doi.org/10.1016/S1470-2045(17)30428-X

    Article  CAS  PubMed  Google Scholar 

  • Lopez AT, Geskin L (2018) A case of nivolumab-induced bullous pemphigoid: review of dermatologic toxicity associated with programmed cell death protein-1/programmed death Ligand-1 inhibitors and recommendations for diagnosis and management. Oncologist. https://doi.org/10.1634/theoncologist.2018-0128

    Article  Google Scholar 

  • Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME (2007) Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12:610–621. https://doi.org/10.1634/theoncologist.12-5-610

    Article  CAS  PubMed  Google Scholar 

  • Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J (2013) Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 27:11–18. https://doi.org/10.1111/j.1468-3083.2012.04546.x

    Article  CAS  PubMed  Google Scholar 

  • Matsumura N, Ohtsuka M, Kikuchi N, Yamamoto T (2016) Exacerbation of psoriasis during nivolumab therapy for metastatic melanoma. Acta Derm Venereol 96:259–260. https://doi.org/10.2340/00015555-2212

    Article  CAS  PubMed  Google Scholar 

  • McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O’Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A (2014) 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 15:323–332. https://doi.org/10.1016/S1470-2045(14)70012-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME (2013) The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol 69:e121–e128. https://doi.org/10.1016/j.jaad.2012.12.963

    Article  CAS  PubMed  Google Scholar 

  • Mochel MC, Hammond MR, Frederick DT, Alora-Palli MB, Piris A, Flaherty KT, Hoang MP (2015) Melanocytic nevi excised during B-Raf proto-oncogene (BRAF) inhibitor therapy: a study of 19 lesions from 10 patients. J Am Acad Dermatol 73:491–499.e2. https://doi.org/10.1016/j.jaad.2015.06.006

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm M-O, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B, CheckMate 214 Investigators (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277–1290. https://doi.org/10.1056/NEJMoa1712126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obara K, Masuzawa M, Amoh Y (2018) Oral lichenoid reaction showing multiple ulcers associated with anti-programmed death cell receptor-1 treatment: a report of two cases and published work review. J Dermatol 45:587–591. https://doi.org/10.1111/1346-8138.14205

    Article  PubMed  Google Scholar 

  • Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS (2003) High frequency of BRAF mutations in nevi. Nat Genet 33:19–20. https://doi.org/10.1038/ng1054

    Article  CAS  PubMed  Google Scholar 

  • Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006–2017. https://doi.org/10.1056/NEJMoa1414428

    Article  PubMed  PubMed Central  Google Scholar 

  • Perier-Muzet M, Thomas L, Poulalhon N, Debarbieux S, Bringuier PP, Duru G, Depaepe L, Balme B, Dalle S, (2014) Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy. J Invest Dermatol 134(5):1351–1358. https://doi.org/10.1038/jid.2013.462.

    Article  CAS  Google Scholar 

  • Rinderknecht JD, Goldinger SM, Rozati S, Kamarashev J, Kerl K, French LE, Dummer R, Belloni B (2013) RASopathic skin eruptions during vemurafenib therapy. PLoS One 8:e58721. https://doi.org/10.1371/journal.pone.0058721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robert C, Arnault J-P, Mateus C (2011a) RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol 23:177–182. https://doi.org/10.1097/CCO.0b013e3283436e8c

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Thomas L, Bondarenko I, O’Day S, Steven MD, Weber J, Garbe C, Lebbe C, Baurain J-F, Testori A, Grob J-J, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen T-T, Humphrey R, Hoos A, Wolchok JD (2011b) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. https://doi.org/10.1056/NEJMoa1104621

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin A-M, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D (2015a) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39. https://doi.org/10.1056/NEJMoa1412690

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015b) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330. https://doi.org/10.1056/NEJMoa1412082

    Article  CAS  PubMed  Google Scholar 

  • Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, KEYNOTE-006 Investigators (2015c) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532. https://doi.org/10.1056/NEJMoa1503093

    Article  CAS  PubMed  Google Scholar 

  • Rofe O, Bar-Sela G, Keidar Z, Sezin T, Sadik CD, Bergman R (2017) Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol 42:309–312. https://doi.org/10.1111/ced.13042

    Article  CAS  PubMed  Google Scholar 

  • Sanlorenzo M, Choudhry A, Vujic I, Posch C, Chong K, Johnston K, Meier M, Osella-Abate S, Quaglino P, Daud A, Algazi A, Rappersberger K, Ortiz-Urda S (2014) Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol 71:1102–1109.e1. https://doi.org/10.1016/j.jaad.2014.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, Lin K, Quaglino P, Rappersberger K, Ortiz-Urda S (2015) Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol 151:1206–1212. https://doi.org/10.1001/jamadermatol.2015.1916

    Article  PubMed  PubMed Central  Google Scholar 

  • Schad K, Baumann Conzett K, Zipser MC, Enderlin V, Kamarashev J, French LE, Dummer R (2010) Mitogen-activated protein/extracellular signal-regulated kinase kinase inhibition results in biphasic alteration of epidermal homeostasis with keratinocytic apoptosis and pigmentation disorders. Clin Cancer Res 16:1058–1064. https://doi.org/10.1158/1078-0432.CCR-09-1766

    Article  CAS  PubMed  Google Scholar 

  • Sibaud V (2018) Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol 19:345–361. https://doi.org/10.1007/s40257-017-0336-3

    Article  PubMed  Google Scholar 

  • Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP (2016) Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 28:254–263. https://doi.org/10.1097/CCO.0000000000000290

    Article  CAS  PubMed  Google Scholar 

  • Siegel DH, Mann JA, Krol AL, Rauen KA (2012) Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. Br J Dermatol 166:601–607. https://doi.org/10.1111/j.1365-2133.2011.10744.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714. https://doi.org/10.1056/NEJMoa1112302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R (2012) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207–215. https://doi.org/10.1056/NEJMoa1105358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weber JS, Flaherty KT, Infante JR, Falchook GS (2012a) Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. J Clin Oncol 30:Suppl.8510.abstract

    Google Scholar 

  • Weber JS, Kähler KC, Hauschild A (2012b) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691–2697. https://doi.org/10.1200/JCO.2012.41.6750

    Article  CAS  PubMed  Google Scholar 

  • Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, Long GV, Li H, Waxman IM, Jiang J, Robert C (2016) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. https://doi.org/10.1200/JCO.2015.66.1389

    Article  CAS  Google Scholar 

  • Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob J-J, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA, 238 Collaborators CM (2017) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1709030

    Article  CAS  Google Scholar 

  • Welsh SJ, Corrie PG (2015) Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol 7:122–136. https://doi.org/10.1177/1758834014566428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R-A, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133. https://doi.org/10.1056/NEJMoa1302369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1709684

    Article  CAS  Google Scholar 

  • Zarbo A, Belum VR, Sibaud V, Oudard S, Postow MA, Hsieh JJ, Motzer RJ, Busam KJ, Lacouture ME (2017) Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol 176:1649–1652. https://doi.org/10.1111/bjd.15237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmer L, Hillen U, Livingstone E, Lacouture ME, Busam K, Carvajal RD, Egberts F, Hauschild A, Kashani-Sabet M, Goldinger SM, Dummer R, Long GV, McArthur G, Scherag A, Sucker A, Schadendorf D (2012) Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol 30:2375–2383. https://doi.org/10.1200/JCO.2011.41.1660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Ramelyte, E., Dummer, R., Libenciuc, C., Phillips, G.S., Lacouture, M.E., Robert, C. (2019). Dermatological Complications of Systemic Therapies for Melanoma. In: Balch, C., et al. Cutaneous Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-319-46029-1_63-1

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