Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance. The addition of a MEK inhibitor can improve blockade of the MAPK pathway and may help to overcome resistance and thereby prolong efficacy, as well as reduce cutaneous toxicity. Combinations of BRAF inhibitors and MEK inhibitors (dabrafenib plus trametinib and vemurafenib plus cobimetinib) have been approved for the treatment of BRAF-mutant metastatic melanoma and may become a new standard of care. However, acquired resistance is still a significant concern with BRAF and MEK inhibitor combination therapy, and other strategies are being investigated, including the use of sequential and intermittent schedules. The combination of BRAF or MEK inhibitors with immunotherapy has been shown to hold considerable promise, with several combinations being evaluated in clinical trials. Preliminary results from clinical trials involving triple combination therapy with BRAF-MEK inhibitors and anti-PD-L1 antibodies appear promising and may indicate a new strategy to treat patients with BRAF-mutated metastatic melanoma. Biomarkers are needed to help identify patients with BRAFV600 mutations most likely to benefit from first-line BRAF/MEK inhibitor therapy rather than immunotherapy and vice versa.
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Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17:1248–60.
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet. 2012;380:358–65.
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.
Johnson DB, Menzies AM, Zimmer L, et al. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur J Cancer. 2015;51:2792–9.
Kim K, Kefford R, Pavlick A, 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.
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.
Flaherty K, Infante J, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Eng J Med. 2012;367:1694–703.
Daud A, Weber J, Sosman J, et al. Updated overall survival (OS) results for BRF113220, a phase I–II study of dabrafenib alone versus combined dabrafenib and trametinib in patients with BRAF V600 metastatic melanoma (MM). J Clin Oncol. 2015;33(Suppl):Abstract 9036.
Long G, Stroyakoversuskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Eng J Med. 2014;371:1877–88.
Schadendorf D, Amonkar MM, Stroyakoversuskiy D, et al. Health-related quality of life impact in a randomized phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015;51:833–40.
Long G, Stroyakoversuskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomized controlled trial. Lancet. 2015;386:444–51.
Flaherty KT, Davies MA, Grob J, et al. Genomic analysis and 3-year efficacy and safety update of COMBI-d. J Clin Oncol. 2016;34(Suppl):abstract 9502.
Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomized trial. Lancet Oncol. 2015;16:1389–98.
Robert C, Karaszewska B, Schachter J, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib and trametinib versus vemurafenib as first-line therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at European Cancer Congress, 2015 Sept 25–29, Vienna. Abstract 3301. http://www.ecco-org.eu/Vienna2015/Scientific-Programme/Searchable-Programme?trackid=00181#anchorScpr. Accessed 29 Sept 2014.
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;15:954–65.
Thakur M, Stuart D. The evolution of melanoma resistance reveals therapeutic opportunities. Cancer Res. 2013;73:6106–10.
Pavlick A, Ribas A, Gonzalez R, et al. Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J Clin Oncol. 2015;33(Suppl):Abstract 9020.
Larkin J, Ascierto P, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.
McArthur GA, Dréno B, Atkinson V, et al. Efficacy of long-term cobimetinib combined with vemurafenib in advanced BRAFV600-mutated melanoma: 3-year follow-up of the phase 3 CoBRIM study and 4-year follow-up of the phase 1b BRIM7 study. Presented at the Society for Melanoma Research 2016 Congress, 2016 Nov 6–9, Boston (MA).
Sullivan R, Weber J, Patel S, 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. 2015;33(Suppl):abstract 9007.
Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS Part 1: a phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in BRAF-mutant melanoma. Presented at the Society for Melanoma Research 2016 Congress, 2016 Nov 6–9, Boston (MA).
Long G, Fung C, Menzies A, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014;5:5694.
Moriceau G, Hugo W, Hong A, et al. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell. 2015;27:240–56.
Mateus C, Routier E, Roy S, et al. Biomarker study evaluating the combination of dabrafenib (D) with trametinib (T) versus the combination after 8 weeks of monotherapy with dabrafenib or trametinib in patients with metastatic and unresectable stage IIIC or IV melanoma: GSK study 116613. J Clin Oncol. 2014;32(Suppl):TPS9114.
Algazi A, Othus M, Daud A, et al. SWOG S1320: a randomized phase II trial of intermittent versus continuous dosing of dabrafenib and trametinib in BRAFV600E/k mutant melanoma. J Clin Oncol. 2015;33(Suppl):TPS9093.
Wilmott J, Long G, Howle J, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1386–94.
Wargo J, Cooper Z, Flaherty K. Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov. 2014;4:1377–86.
Frederick D, Piris A, Cogdill A, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–31.
Schadendorf D, Hodi F, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–94.
Robert C, Schachter J, Long G, et al. The evolution of melanoma resistance reveals therapeutic opportunities. Cancer Res. 2015;73:6106–10.
Hodi FS, Kluger K, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial. Presented at AACR Annual Meeting AACR, 2016 Apr 16–20, New Orleans (LA). doi:10.1158/1538-7445.AM2016-CT001.
Hodi F, O’Day S, Mcdermott D, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.
Hodi F, Sznol M, Kluger H, et al. Long-term survival of ipilimumab-naive patients with advanced melanoma treated with nivolumab in a phase I trial. J Clin Oncol. 2014;32(Suppl):abstract 9002.
Daud A, Ribas A, Robert C, et al. Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001. J Clin Oncol. 2015;33:9005.
Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6.
Hamid O, Patel M, Hodi S, et al. Preliminary clinical safety, tolerability and activity of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600 metastatic melanoma. Pigment Cell Melanoma Res. 2015;28(6):778 (abstract). doi:10.1111/pcmr.12419.
Sullivan RJ, Hamid O, Gonzalez R, et al. Safety and clinical activity of atezolizumab + cobimetinib + vemurafenib in BRAFV600-mutant metastatic melanoma. Presented at the Society for Melanoma Research 2016 Congress, 2016 Nov 6–9, Boston (MA). https://www.melanomacongress.com/docs/2016_abstracts.pdf.
Minor DR, Puzanov I, Callahan MK, Hug BA, Hoos A. Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res. 2015;28:611–2.
Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33(Suppl):Abstract 3003.
Ribas A, Hodi FS, Lawrence DP, et al. Pembrolizumab in combination with dabrafenib and trametinib for B-RAF mutant advanced melanoma: Phase I Keynote-022 study. J Clin Oncol. 2016;34(Suppl):Abstract 3014.
Lau PK, Ascierto PA, McArthur G. Melanoma: the intersection of molecular targeted therapy and immune checkpoint inhibition. Curr Opin Immunol. 2016;39:30–8.
Ascierto PA, Simeone E, Grimaldi AM, et al. Do BRAF inhibitors select for populations with different disease progression kinetics? J Transl Med. 2013;11:61.
Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32:144–9.
Ascierto PA, Simeone E, Giannarelli D, et al. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med. 2012;10:107.
Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120:1695–701.
Daud A, Ribas A, Robert C, et al. Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001. J Clin Oncol. 2015;33(Suppl):Abstract 9005.
Ugurel S, Loquai C, Kähler K, et al. A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival. Ann Oncol. 2015;26:573–82.
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.
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;15:436–44.
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;34:871–8.
McArthur GA, Larkin JM, Ascierto PA, et al. Efficacy of cobimetinib and vemurafenib in patients with advanced BRAF-mutated melanoma with poor and favorable prognosis in the coBRIM phase 3 study. J Clin Oncol. 2016;34(Suppl):Abstract 9350.
Massi D, Brusa D, Merelli B, et al. The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. Ann Oncol. 2015;26:1980–7.
Jiang X, Zhou J, Giobbie-Hurder A, et al. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res. 2013;19:598–609.
Wongchenko MJ, Ribas A, Dréno B, et al. Progression-free and overall survival with cobimetinib (cobi) + vemurafenib (vem) + treatment is independent of PD-L1 expression. Presented at the Society for Melanoma Research 2016 Congress, 2016 Nov 6–9, Boston (MA). https://www.melanomacongress.com/docs/2016_abstracts.pdf.
Festino L, Botti G, Lorigan P, et al. Cancer treatment with anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs. 2016;76:925–45.
Robert C, Long GV, Brady B. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.
Galon J, Fox BA, Bifulco CB, et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med. 2016;14:273.
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.
Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207–11.
Ribas A, Robert C, Hodi FS, et al. Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. J Clin Oncol. 2013;33(Suppl):Abstract 3001.
Yan Y, Robert C, Larkin J, et al. Genomic features of complete responders (CR) versus fast progressors (PD) in patients with BRAFV600-mutated metastatic melanoma treated with cobimetinib + vemurafenib or vemurafenib alone. Ann Oncol. 2016;27(Suppl 6):1111O.
Diaz LA Jr, Le DT. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;373:1979.
Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014–23.
Mittapalli R, Vaidhyanathan S, Dudek A, Elmquist W. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344:655–64.
Long G, Trefzer U, Davies M, 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;13:108795.
Dummer R, Goldinger S, Turtschi C, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50:611–21.
Kefford R, Malo M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open label, single arm, phase 2, multicenter study. Presented at 2013 Society for Melanoma Research Congress, 2013 Nov 17–20, Philadelphia (PA).
Queirolo P, Spagnolo F, Picasso V, et al. Combined vemurafenib and fotemustine in patients with BRAFV600 melanoma progressing on vemurafenib. Oncotarget. 2016. doi:10.18632/oncotarget.10589.
Davies M, Martins K, Sessa T, Swann S. Phase II, open-label study of dabrafenib plus trametinib in patients with BRAF mutation-positive melanoma brain metastases: a GSK-sponsored trial. J Clin Oncol. 2014;32(Suppl):TPS9106.
Yee M, Lin Y, Gorantla V, et al. Phase 2 study of cobimetinib in combination with vemurafenib in active melanoma brain metastases (coBRIM-B). J Clin Oncol. 2015;33(Suppl):TPS9088.
The authors extend special thanks to Alessandra Trocino for providing excellent bibliography service and assistance.
ES and PAA prepared the manuscript collaboratively with input from and the approval of all co-authors. All authors read and approved the final manuscript.
No funding was received for the preparation of this review.
Conflict of interest
ES has participated on an advisory board for Bristol Myers Squibb (BMS) and received honoraria from BMS and Novartis. AMG has participated on an advisory board for Novartis and received honoraria from BMS and Novartis. PAA has had consultant and advisory roles for BMS, Merck Sharp & Dohme, Roche-Genentech, Novartis, Amgen, Array, and Merck-Serono. He has received research funds from BMS, Roche-Genentech, and Array. LF, VV, and MP have no conflicts of interest.
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Simeone, E., Grimaldi, A.M., Festino, L. et al. Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care. BioDrugs 31, 51–61 (2017). https://doi.org/10.1007/s40259-016-0208-z
- Overall Survival
- Brain Metastasis
- Median Overall Survival