American Journal of Clinical Dermatology

, Volume 14, Issue 6, pp 461–471 | Cite as

Cutaneous Adverse Events to Type I BRAF Inhibitors: An Analysis of Effects Associated with Each Inhibitor and Therapeutic Time Interval to Onset

Review Article

Abstract

The treatment of malignant melanoma with inhibitors targeting the BRAF V600E mutation has demonstrated dramatic clinical and radiographic response with improved progression-free and overall survival in the majority of patients receiving treatment. However, cutaneous adverse effects—from proliferative processes to more classic drug side effects—are increasingly being reported in patients on BRAF inhibitors. In this comprehensive literature review we provide (1) an all-inclusive list of cutaneous adverse effects associated with selective class I RAF inhibitors, (2) specific adverse effects associated with each inhibitor, and (3) the therapeutic time interval associated with the onset of all reported lesion types. Twenty-two studies reporting cutaneous adverse reactions with selective class I RAF inhibitor therapy were retrieved from PubMed and sourced from relevant articles referenced by other papers. We identified over 45 differently described lesion types, corresponding to close to 2,000 cases. The most commonly reported lesion types in order of decreasing frequency include inflammatory dermatoses, benign lesions, malignant lesions, and hair/nail-related abnormalities. For the most part, the terminologies used in the original studies were retained. Case totals and time-to-lesion onset are presented for every group, and where available, for individual lesion types, by associated BRAF inhibitor.

References

  1. 1.
    Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.PubMedCrossRefGoogle Scholar
  2. 2.
    Sosman JA, Kim KB, Schuchter L, Gonzalez R, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.PubMedCrossRefGoogle Scholar
  4. 4.
    Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.PubMedCrossRefGoogle Scholar
  5. 5.
    Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.PubMedCrossRefGoogle Scholar
  6. 6.
    Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    Belum VR, Fischer A, Choi JN, Lacouture ME. Dermatological adverse events from BRAF inhibitors: a growing problem. Curr Oncol Rep. 2013;15(3):249–59.PubMedCrossRefGoogle Scholar
  10. 10.
    Pappas-Taffer L, Rosenbach M, Chu EY. The cutaneous side effects of selective BRAF inhibitors and anti-CTLA4 agents: the growing role of the dermatologist in the management of patients with metastatic melanoma. Curr Dermatol Rep. 2013:1–17.Google Scholar
  11. 11.
    Chapman PB, Hauschild A, Robert C, et al. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.PubMedCrossRefGoogle Scholar
  12. 12.
    Sinha R, Edmonds K, Newton-Bishop JA, et al. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol. 2012;167:987–94.PubMedCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    Huang V, Hepper D, Anadkat M, Cornelius L. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol. 2012;148:628–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Mattei PL, Alora-Palli MB, Kraft S, Lawrence DP, et al. Cutaneous effects of BRAF inhibitor therapy: a case series. Ann Oncol. 2012 (Epub ahead of print).Google Scholar
  16. 16.
    Wang CM, Fleming KF, Hsu S. A case of vemurafenib-induced keratosis pilaris-like eruption. Dermatol Online J. 2012;18:7.PubMedGoogle Scholar
  17. 17.
    Flaherty KT. Building on BRAF inhibition in melanoma and extending to other cancers. Presented at the ASCO Annual Meeting, Chicago, IL, USA. 2011.Google Scholar
  18. 18.
    Alloo A, Garibyan L, LeBoeuf N, Lin G, Werchniak A, Hodi FS Jr, Flaherty KT, Lawrence DP, Lin JY, et al. Photodynamic therapy for multiple eruptive keratoacanthomas associated with vemurafenib treatment for metastatic melanoma. Arch Dermatol. 2012;148:363–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Ezra N, Hamid O, Behroozan D. Eruptive squamous cell carcinomas associated with BRAF-inhibitor therapy in a patient with metastatic melanoma. Dermatol Surg. 2012;38:1086–90.PubMedCrossRefGoogle Scholar
  20. 20.
    Harvey NT, Millward M, Wood BA. Squamoproliferative lesions arising in the setting of BRAF inhibition. Am J Dermatopathol. 2012;34:822–6.PubMedCrossRefGoogle Scholar
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    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(3):207–15.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    Trefzer U, Minor D, Ribas A, et al. BREAK-2: a phase IIA trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF mutation-positive (V600E/K) metastatic melanoma. Pigment Cell Melanoma Res. 2011;24:1020 (abstract).Google Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    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. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol. 2013;24(6):1691–7.Google Scholar
  28. 28.
    Rinderknecht JD, Goldinger SM, Rozati S, Kamarashev J, Kerl K, French LE, Dummer R, Belloni B. RASopathic skin eruptions during vemurafenib therapy. PLoS One. 2013;8(3):e58721.PubMedCrossRefGoogle Scholar
  29. 29.
    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. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. 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(11):1087–95.PubMedCrossRefGoogle Scholar
  31. 31.
    Hauschild A, Grob J-J, Demidov LV, et al. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600 E-mutated melanoma. Proc Am Soc Clin Oncol. 2012; 30(suppl): LBA8500 (abstr).Google Scholar
  32. 32.
    Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013;14(1):e11–8.Google Scholar
  33. 33.
    Dalle S, Poulalhon N, Thomas L. Vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;365(15):1448–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Dermatopathology Section, Department of DermatologyBoston University School MedicineBostonUSA

Personalised recommendations