Molecularly targeted therapy for metastatic melanoma
- Jeffrey A Sosman, MD
Jeffrey A Sosman, MD
- Professor of Medicine
- Robert H. Lurie Comprehensive Cancer Center of Northwestern
Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. In that setting, surgical excision is curative in most cases, and patients at high risk of developing metastatic disease may benefit from adjuvant immunotherapy with interferon alpha or ipilimumab (algorithm 1) . (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant immunotherapy for melanoma".)
The management of patients with disseminated disease is a difficult problem (algorithm 2). Approaches that have been shown to provide clinically important benefit for appropriately selected patients with disseminated melanoma include immunotherapy with high-dose interleukin-2 (IL-2), immunotherapy with antibodies targeting programmed cell death protein 1 (PD-1) and/or with ipilimumab (a monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), and inhibition of the mitogen-activated protein (MAP) kinase pathway in patients whose tumors contain a V600 mutation in the BRAF gene using either a BRAF inhibitor or an MEK inhibitor. There are no randomized trials that compare targeted therapy with immunotherapy, and there are no prospective data on the appropriate sequencing of these therapies for patients with a BRAFV600 mutation.
The use of targeted therapies in the treatment of advanced melanoma will be reviewed here.
APPROACH TO TREATMENT
An understanding of the role of activation of the mitogen-activated protein (MAP) kinase pathway has led to the identification of several drug targets (figure 1). This is resulting in the development of important therapeutic approaches for the treatment of advanced melanoma in various patient subsets. These include inhibition of BRAF, MEK, NRAS, and KIT.
The general approach to the treatment of advanced melanoma and the integration of targeted therapy with other treatment modalities is presented separately (algorithm 2). (See "Overview of the management of advanced cutaneous melanoma" and "The molecular biology of melanoma".)
- Cole BF, Gelber RD, Kirkwood JM, et al. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1996; 14:2666.
- Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol 2010; 80:561.
- Smalley KS, Sondak VK. Melanoma--an unlikely poster child for personalized cancer therapy. N Engl J Med 2010; 363:876.
- Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29:1239.
- 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.
- Sosman JA, Pavlick AC, Schuchter LM, et al. Analysis of molecular mechanisms of response and resistance to vemurafenib (vem) in BRAFV600E melanoma (abstract #8503). J Clin Oncol 2012. 30s.
- McArthur GA, Chapman PB, Robert C, 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; 15:323.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202806s000lbl.pdf (Accessed on May 30, 2013).
- 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.
- Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: Dabrafenib versus dacarbazine in patients with BRAF V600E-positive mutation metastatic melanoma (Abstract 9013). American Society of Clinical Oncology 2013 meeting.
- Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014; 15:436.
- Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013; 14:e11.
- 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.
- Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist 2013; 18:314.
- Chapman PB, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol 2012.
- Zimmer L, Haydu LE, Menzies AM, et al. Incidence of new primary melanomas after diagnosis of stage III and IV melanoma. J Clin Oncol 2014; 32:816.
- 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.
- Carlos G, Anforth R, Clements A, et al. Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. JAMA Dermatol 2015; 151:1103.
- Callahan MK, Rampal R, Harding JJ, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 2012; 367:2316.
- Choe CH, McArthur GA, Caro I, et al. Ocular toxicity in BRAF mutant cutaneous melanoma patients treated with vemurafenib. Am J Ophthalmol 2014; 158:831.
- Anker CJ, Grossmann KF, Atkins MB, et al. 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; 95:632.
- Klein O, Ribas A, Chmielowski B, et al. Facial palsy as a side effect of vemurafenib treatment in patients with metastatic melanoma. J Clin Oncol 2013; 31:e215.
- Launay-Vacher V, Zimner-Rapuch S, Poulalhon N, et al. Acute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients. Cancer 2014; 120:2158.
- Regnier-Rosencher E, Lazareth H, Gressier L, et al. Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas. Br J Dermatol 2013; 169:934.
- Uthurriague C, Thellier S, Ribes D, et al. Vemurafenib significantly decreases glomerular filtration rate. J Eur Acad Dermatol Venereol 2014; 28:978.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204114s000lbl.pdf (Accessed on May 30, 2013).
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367:107.
- Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013; 14:249.
- Ascierto PA, et al. Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations (abstract #8511). J Clin Oncol 2012.
- Dummer R,Schadendorf D, Ascierto PA, et al. Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. Abstract 9500, 2016 American Society of Clinical Oncology meeting.
- Sosman JA, Kittaneh M, Lolkema MP, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity (abstract 9009). 2014 American Society of Clinical Oncology meeting.
- Purbrick RM, Osunkunle OA, Talbot DC, Downes SM. Ocular Toxicity of Mitogen-Activated Protein Kinase Inhibitors. JAMA Oncol 2016.
- 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.
- Flaherty K, Daud A, Weber JS, et al. Updated overall survival (OS) for BRF113220, a phase 1-2 study of dabrafenib (D) alone versus combined dabrafenib and trametinib (D+T) in pts with BRAF V600 mutation-positive (+) metastatic melanoma (MM) (abstract 9010). 2014 American Society of Clinical Oncology (ASCO) meeting.
- Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371:1877.
- Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015; 386:444.
- Flatherty K, Davies MA, Grob JJ, et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: A phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Abstract 9502 American Society of Clinical Oncology meeting.
- Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30.
- Robert C, Karaszewska B, Schacter J, ert al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib + trametinib in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma (abstract LBA40). Presented at the 2016 European Society for Medical Oncology meeting.
- Long GV, Weber JS, Infante JR, et al. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J Clin Oncol 2016; 34:871.
- Long GV, Grob JJ, Nathan P, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol 2016.
- Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol 2014; 15:954.
- Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371:1867.
- Larkin JM, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol 33, 2015 (suppl; abstr 9006)
- Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016; 17:1248.
- Sullivan RY, Weber JS, Patel SP, et al. A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. J Clin Oncol 33, 2015 (suppl; abstr 9007)
- Penel N, Delcambre C, Durando X, et al. O-Mel-Inib: a Cancéro-pôle Nord-Ouest multicenter phase II trial of high-dose imatinib mesylate in metastatic uveal melanoma. Invest New Drugs 2008; 26:561.
- Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006; 106:2005.
- Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005; 92:1398.
- Flaherty KT, Brose M, Schuchter L. Phase I/II trial of BAY 43-9006, carboplatin and paclitaxel demonstrates preliminary amtotumor activity in the expansion cohort of patients with metastatic melanoma. Proc Am Soc Clin Oncol 2004; 23:708a.
- Amaravadi RK, Schuchter LM, McDermott DF, et al. Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases. Clin Cancer Res 2009; 15:7711.
- Eisen T, Marais R, Affolter A, et al. Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies. Br J Cancer 2011; 105:353.
- Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2009; 27:2823.
- Flaherty KT, Lee SJ, Zhao F, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 2013; 31:373.
- Fruehauf J, Lutzky J, McDermott D, et al. Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res 2011; 17:7462.
- Varker KA, Biber JE, Kefauver C, et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Ann Surg Oncol 2007; 14:2367.
- González-Cao M, Viteri S, Díaz-Lagares A, et al. Preliminary results of the combination of bevacizumab and weekly Paclitaxel in advanced melanoma. Oncology 2008; 74:12.
- Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer 2009; 115:119.
- Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 2012; 30:34.
- APPROACH TO TREATMENT
- Mutation status of tumor
- BRAF INHIBITION
- Brain metastases
- Toxicity from BRAF inhibition
- - Cutaneous toxicity and secondary tumors
- - Other toxicities
- MEK INHIBITION
- Other MEK inhibitors
- - Cobimetinib
- - Binimetinib
- Toxicity of MEK inhibitors
- COMBINED MEK PLUS BRAF INHIBITION
- Dabrafenib plus trametinib
- Vemurafenib plus cobimetinib
- Encorafenib plus binimetinib
- KIT INHIBITION
- SUMMARY AND RECOMMENDATIONS