Skip to main content

Advertisement

SpringerLink
Log in

Managing The Skin Toxicities From New Melanoma Drugs

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

Opinion Statement

Patients treated with ipilimumab or targeted inhibitors of the RAF-MEK-ERK pathway (vemurafenib, dabrafenib, and trametinib) for advanced cutaneous melanoma often experience drug-related skin toxicities denoted as dermatologic adverse events (DAEs). Although rarely life-threatening, DAEs may emerge dramatically and potentially compromise oncologic therapy if not managed in a timely and effective manner. Early recognition of DAEs is critical to providing optimal skin care and prompt consultation with a dermatologist should be obtained when a diagnosis is unclear. The expanding utilization of new melanoma drugs compels physicians to maintain a watchful eye for both known and novel DAEs and to adopt a low threshold to biopsy worrisome skin findings. Numerous therapeutic options are available to manage DAEs including topical and systemic agents as well as surgical and destructive modalities. Applying such methods improves overall patient care and optimizes the effectiveness of new therapies for advanced cutaneous melanoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

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

  1. Siegel R, Ma J, Zou Z, et al. Cancer statistics 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  2. Dickson PV, Gershenwald JE. Staging and prognosis of cutaneous melanoma. Surg Oncol Clin N Am. 2011;20:1–17.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Wolchok J, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with previously treated, advanced melanoma: a randomized, double-blind, multicenter, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64.

    Article  CAS  PubMed  Google Scholar 

  4. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Voskens CJ, Goldinger SM, Loquai C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8:e53745:1–17. This is an excellent report on rare DAEs associated with ipilimumab and associated treatment recommendations.

  6. YERVOY (Ipilimumab) Product insert revised. December, 2013.

  7. McArthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol. 2013;31:499–506.

    Article  CAS  PubMed  Google Scholar 

  8. Ibrahim R, Berman D, de Pril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29: [Abstract no. 8583].

  9. Choi JN. How to recognize and manage ipilimumab-induced dermatologic adverse events. The ASCO Post. 2013;4. An excellent article offering practical treatment recommendations for ipilimumab-induced DAEs.

  10. National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events Version 3.0. 2006: p.14–6. Available at: http://ctep.cancer.gov.

  11. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology 3rd Edition. 2012. ISBN-13: 9780723435716. Erythema Multiforme, Stevens-Johnson syndrome, and Toxic Epidermal Necrolysis Elsevier Health Sciences Publisher. 2012; Chapter 20:

  12. Ensslin CJ, Rosen AC, Wu S, et al. Pruritis in patients treated with targeted cancer therapies: systematic review and meta-analysis. J Am Acad Dermatol. 2013;69:708–20.

    Article  PubMed  Google Scholar 

  13. Pintova S, Sidhu H, Friedlander PA, et al. Sweet’s syndrome in a patient with metastatic melanoma after ipilimumab therapy. Melanoma Res. 2013;23:498–501.

    Article  PubMed  Google Scholar 

  14. Deylon J, Mateus C, Lambert T. Hemophilia A Induced by Ipilimumab. N Engl J Med. 2011;365:1747–8.

    Article  Google Scholar 

  15. Assi H, Wilson KS. Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: 2 illustrative cases. Curr Oncol. 2013;20:e165–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. “YERVOY (ipilimumab): Immune-mediated Adverse Reaction Management Guide,” Risk Evaluation and Mitigation Strategy (REMS), Bristol-Myers Squibb, 2011. Available at: https://www.hcp.yervoy.com/pdf/rems-management-guide.pdf.

  17. Eckert A, Schoeffler A, Dalle S, et al. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology. 2009;218:69–70.

    Article  CAS  PubMed  Google Scholar 

  18. Vogel WV, Guislain A, Kvistborg P, et al. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012;30:e7–10.

    Article  PubMed  Google Scholar 

  19. Berthod G, Lazor R, Letovanec I, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30:e156–9.

    Article  PubMed  Google Scholar 

  20. ZELBORAF (Vemurafenib) Product Insert Revised July, 2013.

  21. Platz A, Egyhazi S, Ringborg U, et al. Human cutaneous melanoma: a review of NRAS and BRAF mutation frequencies in relation to histogenic subclass and body site. Mol Oncol. 2008;1:395–405.

    Article  PubMed  Google Scholar 

  22. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patient with melanoma. Oncologist. 2013;18:314–22. An excellent comprehensive analysis of DAEs associated with vemurafenib.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Boussemart L, Routier E, Mateus C, et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol. 2013;24:1691–7. A well conducted small prospective study on DAEs associated with vemurafenib.

    Article  CAS  PubMed  Google Scholar 

  25. Mattei PL, Alora-Palli MB, Kraft S, et al. Cutaneous effects of BRAF inhibitor therapy: a case series. Ann Oncol. 2013;24:530–7. A thorough and very detailed retrospective analysis of DAEs experienced by 33 patients treated with either vemurafenib or dabrafenib/trametinib combination therapy.

    Article  CAS  PubMed  Google Scholar 

  26. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30:316–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Sambrano BL, Riddel CE, Chon SY. Eruptive milia secondary to vemurafenib. J Am Acad Dermatol. 2013;69:e258–60.

    Article  PubMed  Google Scholar 

  31. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.

    Article  CAS  PubMed  Google Scholar 

  32. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703. doi:10.1056/NEJMoa1210093. A landmark clinical trial demonstrating the protective effect of trametinib against new onset KAs/SCCs induced by dabrafenib.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  35. Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013;14:e11–8.

    Article  CAS  PubMed  Google Scholar 

  36. Zimmer L, Hillen U, Livingstone E, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol. 2012;30:2375–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Dalle S, Poulalhon N, Thomas L. Vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;365:1450.

    Article  Google Scholar 

  38. Cohen PR, Bedikian AY, Kim KB. Appearance of new vemurafenib-associated melanocytic nevi on normal-appearing skin: case series and a review of changing or new pigmented lesions in patients with metastatic malignant melanoma after initiating treatment with vemurafenib. J Clin Anesth Dermatol. 2013;6:27–37. A comprehensive up-to-date listing of vemurafenib-induced DAEs providing important details regarding evolution of new melanomas in patients treated with vemurafenib.

    Google Scholar 

  39. Dalle S, Poulalhon N, Debarbieux S, et al. Tracking of second primary melanomas in vemurafenib-treated patients. JAMA Dermatol. 2013;149:488–90.

    Article  CAS  PubMed  Google Scholar 

  40. Boyd KP, Vincent B, Andea A, et al. Nonmalignant cutaneous findings associated with vemurafenib use in patients with metastatic melanoma. J Am Acad Dermatol. 2012;67:1375–9.

    Article  CAS  PubMed  Google Scholar 

  41. Wang CM, Fleming KF, Hsu S. A case of vemurafenib-induced keratosis pilaris-like eruption. Dermatol Online J. 2012;18:7.

    PubMed  Google Scholar 

  42. Rinderknecht JD, Goldinger SM, Rozati S, et al. RASopathic Skin Eruptions during Vemurafenib Therapy. PLoS One. 2013;8:e58721:1–11. A very useful article providing excellent clinical photographs and treatment recommendations for common DAEs associated with vemurafenib.

  43. Harding JJ, Pulitzer M, Chapman PB. Vemurafenib sensitivity skin reaction after ipilimumab. N Engl J Med. 2012;366:866–8.

    Article  CAS  PubMed  Google Scholar 

  44. Wenk KS, Pichard DC, Nasabzadeh T, et al. Vemurafenib-Induced DRESS. JAMA Dermatol. 2013;149:1242–3.

    Article  PubMed  Google Scholar 

  45. Sinha R, Lecamwasam K, Purshouse K, et al. Toxic epidermal necrolysis in a patient receiving vemurafenib for treatment of metastatic malignant melanoma. Br J Dermatol. 2013. doi:10.1111/bjd.12796.

    Google Scholar 

  46. Chu EY, Wanat KA, Miller CJ, et al. Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study. J Am Acad Dermatol. 2012;67:1265–72.

    Article  CAS  PubMed  Google Scholar 

  47. Story SG, Beschloss JK, Dolan CK, et al. Eccrine squamous syringometaplasia associated with vemurafenib therapy. J Am Acad Dermatol. 2012;67:e208–10.

    Article  PubMed  Google Scholar 

  48. Dummer R, Rinderknecht J, Goldinger SM, et al. Ultraviolet A and photosensitivity during vemurafenib therapy. N Engl J Med. 2012;366:480–1.

    Article  CAS  PubMed  Google Scholar 

  49. Gelot P, Dutartre H, Khammari A, et al. Vemurafenib: an unusual UVA-induced photosensitivity. Exp Dermatol. 2013;22:297–8.

    Article  CAS  PubMed  Google Scholar 

  50. Schultze B, Meissner M, Wolter M, et al. Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Strahlenther Onkol. 2013. doi:10.1007/s00066-013-0474-3.

    PubMed  Google Scholar 

  51. Satzger I, Degen A, Asper H, et al. Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy. J Clin Oncol. 2013;31:e220–2.

    Article  PubMed  Google Scholar 

  52. Park JJ, Hawryluk EB, Tahan SR, et al. Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol. 2013. doi:10.1001/jamadermatol.2013.7919.

    Google Scholar 

  53. Degen A, Volker B, Kapp A, et al. Erythema nodosum in a patient undergoing vemurafenib therapy for metastatic melanoma. Eur J Dermatol. 2013;23:118. doi:10.1684/ejd.2012.1915.

    PubMed  Google Scholar 

  54. Sinha R, Edmonds K, Newton-Bishop J, et al. Erythema nodosum-like panniculitis in patients with melanoma treated with vemurafenib. J Clin Oncol. 2013;31:320–1.

    Article  Google Scholar 

  55. Zimmer L, Livingstone E, Hillen U, et al. Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management. Arch Dermatol. 2012;148:357–61.

    Article  CAS  PubMed  Google Scholar 

  56. Novoa RA, Honda K, Koon HB, et al. Vasculitis and panniculitis associated with vemurafenib. J Am Acad Dermatol. 2012;67:e271–2.

    Article  PubMed  Google Scholar 

  57. Maldonado-Seral C, Berros-Fombella JP, Vivanco-Allende B, et al. Vemurafenib-associated neutrophilic panniculitis: an emergent adverse effect of variable severity. Dermatol Online. 2013;19:16.

    Google Scholar 

  58. FDA news release, May 29, 2013: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm354199.htm.

  59. FDA news release, January 10, 2014: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm381159.htm.

  60. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–901.

    Article  CAS  PubMed  Google Scholar 

  61. Ascierto PA, Minor D, Ribas A, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31:3205–11. doi:10.1200/JCO.2013.49.8691.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–95. doi:10.1016/S1470-2045(12)70431-X.

    Article  CAS  PubMed  Google Scholar 

  64. Anforth RM, Blumetti TC, Kefford RF, et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol. 2012;167:1153–60. doi:10.1111/j.1365-2133.2012.11155.x. A useful and comprehensive analysis of common and uncommon DAEs associated with dabrafenib therapy.

    Article  CAS  PubMed  Google Scholar 

  65. Kim KB, Kefford R, Pavlick AC, et al. 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. 2013;31:482–9. doi:10.1200/JCO.2012.43.5966.

    Article  CAS  PubMed  Google Scholar 

  66. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782–9. doi:10.1016/S1470-2045(12)70269-3.

    Article  CAS  PubMed  Google Scholar 

  67. Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773–81. doi:10.1016/S1470-2045(12)70270-X.

    Article  CAS  PubMed  Google Scholar 

  68. Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013;857519.

  69. Gupta AK, Paquet M, Villanueva E, et al. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;12, CD004415. doi:10.1002/1465185.CD004415.pub2.

    PubMed  Google Scholar 

  70. Sachse MM, Wagner G. Clearance of BRAF inhibitor-associated keratoacanthomas by systemic retinoids. Br J Dermatol. 2013. doi:10.1111/bjd.12659.

    Google Scholar 

  71. Anforth R, Blumetti TC, Clements A, et al. Systemic retinoids for the chemoprevention of cutaneous squamous cell carcinoma and verrucal keratosis in a cohort of patients on BRAF inhibitors. Br J Dermatol. 2013;169:1310–3.

    Article  CAS  PubMed  Google Scholar 

  72. Anforth R, Blumetti TC, Mohd Affandi A, et al. Systemic retinoid therapy for chemoprevention of nonmelanoma skin cancer in a patient treated with vemurafenib. J Clin Oncol. 2012;30:e165–7.

    Article  CAS  PubMed  Google Scholar 

  73. Roujeau, JC. Drug reaction with eosinophilia and systemic symptoms (DRESS). UpToDate. Last updated: Nov. 12, 2013. Available at: http://www.uptodate.com/contents/drug-reaction-with-eosinophilia-and-systemic-symptoms-dress.

  74. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology 3rd Edition. 2012. ISBN-13: 9780723435716. Cysts. Elsevier Health Sciences Publisher. 2012; Chapter 110.

  75. Fischer A, Rosen AC, Ensslin CJ, et al. Pruritis to anticancer agents targeting the EGFR, BRAF, and CTLA-4. Dermatol Ther. 2013;26:135–48. The authors provide very user-friendly treatment algorithms for rash, xerosis, and pruritis.

    Article  PubMed  Google Scholar 

  76. Tsunoda K, Onodera H, Akasaka T. Case of malignant melanoma associated with a sarcoid reaction. J Dermatol. 2011;38:939–42.

    CAS  PubMed  Google Scholar 

  77. Rochet NM, Chavan RN, Cappel MA, et al. Sweet syndrome: clinical presentation, associations, and response to treatment in 77 patients. J Am Acad Dermatol. 2013;69:557–64.

    Article  CAS  PubMed  Google Scholar 

  78. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology 3rd Edition. 2012. ISBN-13: 9780723435716. Neutrophilic Dermatoses. Elsevier Health Sciences Publisher. 2012; Chapter 26.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

John C. Mavropoulos and Timothy S. Wang declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

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

Author information

Authors and Affiliations

  1. Department of Dermatology, Johns Hopkins Outpatient Center, Johns Hopkins University, 601 N. Caroline Street, Baltimore, MD, 21287, USA

    John C. Mavropoulos MD, MPH, PhD & Timothy S. Wang MD

Authors
  1. John C. Mavropoulos MD, MPH, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy S. Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John C. Mavropoulos MD, MPH, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mavropoulos, J.C., Wang, T.S. Managing The Skin Toxicities From New Melanoma Drugs. Curr. Treat. Options in Oncol. 15, 281–301 (2014). https://doi.org/10.1007/s11864-014-0284-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-014-0284-6

Keywords

Search

Navigation