The combination of a BRAF and MEK inhibitor are highly active in BRAFV600 mutant melanoma and, along with the checkpoint inhibitors targeting PD1 and CTLA-4, form the standard of care for BRAF-mutant melanoma.
Evidence included from outside the systematic review is identified with an asterisk (*) following the reference.
Systematic review evidence
Single agent BRAF inhibitor
Two randomised phase III studies have compared the single agent BRAF inhibitors vemurafenib and dabrafenib to chemotherapy in treatment-naïve V600 BRAF-mutant positive patients. In the BRIM-3 study patients with BRAFV600E mutant melanoma were randomized to either vemurafenib 960mg twice a day or dacarbazine. As compared to dacarbazine, vemurafenib was associated with an improvement in overall response rate (48% vs 5%, P<0.001), progression-free survival (PFS; median 5.3 vs 1.6 months, HR 0.26, P<0.001) and overall survival (OS; HR 0.37, P<0.001). Similarly dabrafenib 150mg bd improved the response rate (50% vs 6%) and PFS (median 5.1 vs 2.7 months, HR 0.30, p<0.0001) compared to dacarbazine. Unlike the vemurafenib study, OS did not differ between the two arms of the study, a difference attributable to the dabrafenib study allowing cross-over for those who progressed on dacarbazine rather than any difference in efficacy between the drugs. The single agent study of dabrafenib BRAF inhibitors limited enrolment to patients whose tumours had a BRAFV600E mutation, whereas the vemurafenib study allowed any V600 mutation detected by the study screening test (which was design to be highly sensitive and specific for V600E). However both vemurafenib and dabrafenib are active in other BRAFV600 mutations, but not non-V600 mutations.*
Single agent MEK inhibitor
The MEK inhibitor trametinib was compared to decarbazine in a phase III study and improved both PFS (median 4.8 vs 1.5 months HR 0.45 P<0.001) and OS (HR 0.54, P=0.01). Despite the positive study, single agent trametinib is not considered an appropriate treatment in BRAFV600 mutant melanoma given its inferior efficacy (response rate 22%) and toxicity compared with single agent BRAF inhibitor or combination BRAF/MEK inhibition (see below).
Combination BRAF/MEK inhibition
Three published phase III studies have compared combination BRAF/MEK inhibition with single agent BRAF inhibitor. Combination dabrafenib plus trametinib, as compared to dabrafenib plus placebo, improved the PFS (median 9.3 vs 8.8 months, HR 0.75, P = 0.03) and overall response rate (P = 0.002). Similarly dabrafenib and trametinib as compared with vemurafenib improved PFS (median 11.4 vs 7.3 months, HR 0.56, P<0.001) and OS (HR 0.69, P=0.005). Combination vemurafenib and cobimetinib as compared with single agent vemurafenib improved the PFS (median 9.9 vs 6.2 months, HR 0.51, P<0.001)REF? 30 and OS (HR 0.70 p=0.005). In a pooled analysis* of both the combination dabrafenib/trametinib phase III studies, the combination has a landmark 1-, 2- and 3-year PFS of 48%, 30% and 23%, respectively. Landmark OS at 1, 2 and 3 years was 74%, 53% and 44%, respectively.*
Combination dabrafenib/trametinib and vemurafenib/cobimetinib despite not being compared directly are likely to have comparable efficacy, and there is no evidence that one combination can overcome failure of the other. A number of prognostic factors impact on duration of response and OS, a normal LDH and less than three organ sites involved is associated with a prolonged PFS.* An elevated LDH, particularly one >2-fold upper limit of normal is associated with a shorter PFS and OS.*
Combination dabrafenib/trametinib was associated with grade 3 or 4 adverse events in 35% of patients. Combination vemurafenib/cobimetinib was associated with a 65% rate of grade 3 or 4 adverse events. The two combinations have different toxicity profiles, vemurafenib/cobimetinib is associated with a risk of photosensitivity and hepatotoxicity (most commonly a transaminitis) while dabrafenib/trametinib commonly causes treatment related pyrexia syndrome. Over half of all patients treated with combination dabrafenib/trametinib will develop pyrexia syndrome defined as one or more of the following: fever (≥38°C); Chills/rigors/nightsweats; Flu-like symptoms. Initial management of pyrexia syndrome involves treatment interruption. In the setting of recurrent fevers, intermittent dosing and/or corticosteroids may be used.
MEK inhibition in NRAS mutant melanoma
The MEK inhibitor binimetinib was compared to dacarbazine in a phase III study in patients with NRAS Q61 mutant melanoma. Binimetinib was associated with an improvement in PFS (2.8 vs 1.5 months, HR 0.62, P<0.001). There was no significant difference in OS (HR 1.00, P=0.50). Of interest the benefit of binimetinib appeared greatest in patients who received prior immunotherapy. MEK inhibitors are associated with a range of toxicities, including most frequently an acneiform rash, nausea and diarrhea, less commonly cardiac or ocular toxicities can occur.
| TARGETED THERAPY: V600 BRAF Mutation-Positive Melanoma
First-line/upfront combined therapy with a BRAF inhibitor and MEK inhibitor (dabrafenib + trametinib or vemurafenib + cobimetinib) improves the response rate, progression-free survival (PFS) and overall survival compared with BRAF inhibitor monotherapy in patients whose melanoma has a BRAFV600 mutation.
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| TARGETED THERAPY: Q61 NRAS Mutation-Positive Melanoma
First- and second-line MEK inhibitor (binimetinib) improves the response rate and progression-free survival, but not the overall survival compared with dacarbazine chemotherapy in patients whose melanoma has an NRAS Q61 mutation.
Next section: Chemotherapy
See the Summary of all recommendations section for all recommendations and practice points.
- Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011 Jun 30;364(26):2507-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21639808.
- Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012 Jul 28;380(9839):358-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22735384.
- Carlino MS, Long GV, Kefford RF, Rizos H. Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma. Crit Rev Oncol Hematol 2015 Dec;96(3):385-98 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26358420.
- Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012 Jul 12;367(2):107-14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22663011.
- Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014 Nov 13;371(20):1867-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25265494.
- Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014 Nov 13;371(20):1877-88 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25265492.
- Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015 Jan 1;372(1):30-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25399551.
- Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer 2017 Sep;82:45-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28648698.
- Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, 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 Dec;17(12):1743-1754 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27864013.
- Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, 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 Sep;17(9):1248-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27480103.
- Atkinson V, Long GV, Menzies AM, McArthur G, Carlino MS, Millward M, et al. Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists. Asia Pac J Clin Oncol 2016 Dec;12 Suppl 7:5-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27905182.
- Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017 Apr;18(4):435-445 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28284557.
- Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, 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 Aug 1;386(9992):444-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26037941.