Preliminary evidence of efficacy for BRAF inhibitors as monotherapy in advanced melanoma first emerged in 2009.1 Phase II and III trials rapidly ensued for vemurafenib (Zelboraf) and dabrafenib (Tafinlar), leading to U.S. Food and Drug Administration (FDA) approval in 2011. As a result of melanoma field–wide collaboration investigating mechanisms of resistance and the basis for the frequently observed proliferative skin lesions, a strategy to combine MEK inhibitors with BRAF inhibitors to overcome both shortcomings was devised. In a remarkably short period of time, this translational research yielded proof-of-concept in 2012 and FDA approval of the first BRAF/MEK inhibitor combination regimen in early 2014.2
Recently, three phase III trials have corroborated the reproducible benefit of combined BRAF/MEK inhibition in extending progression-free and overall survival compared to BRAF inhibitor monotherapy.3-5 While it took 9 years to establish BRAF inhibitor monotherapy as a treatment standard following the discovery of BRAF mutations in approximately half of melanoma patients, only three additional years were needed to establish the benefit of BRAF inhibitor–based combination therapy.
Underlying Mechanisms
The two FDA-approved BRAF inhibitors, vemurafenib and dabrafenib, have nearly identical efficacy parameters in a V600-mutant BRAF metastatic melanoma population: 50% to 60% objective response rates, median progression-free survival of 6 to 7 months, and 1-year survival rates of approximately 55%.6,7 Laboratory investigations of human melanoma models and patient tumor specimens have demonstrated that reactivation of the MAP kinase pathway (which is constitutively activated as a consequence of BRAF mutation) can be found in approximately two-thirds of patients whose tumors are analyzed at the time of acquired resistance to a BRAF inhibitor.8
A variety of molecular mechanisms have been described to account for this, with the most common being alternative splicing of BRAF, emergence of tumor cells with coexisting BRAF and NRAS mutations, BRAF amplification, and MEK mutation.9-12 Each of these mechanisms pointed to reactivation of MEK and ERK signaling (components of the MAP kinase pathway downstream of BRAF) and suggested that targeting MEK or ERK might provide benefit at the time of acquired resistance.
Unfortunately, single-agent MEK inhibition does not demonstrate significant efficacy for patients who have just experienced disease progression on a BRAF inhibitor. Modest activity was demonstrated for combinations adding MEK inhibitors to either dabrafenib or vemurafenib in the BRAF inhibitor–refractory context.13 Notably, the MEK inhibitor trametinib (Mekinist) has demonstrated single-agent efficacy in BRAF-mutant melanoma and was FDA approved for the treatment of BRAF V600–mutant melanoma.14 But, numerous investigational MEK inhibitors with properties very similar to trametinib are available for inclusion in a BRAF/MEK combination regimen; thus, cobimetinib has been investigated for use in combination with vemurafenib.
Dual Inhibitor Trials
The first evidence corroborating the hypothesis that the addition of a MEK inhibitor to a BRAF inhibitor in a BRAF inhibitor–naive population came in the form of a phase I/randomized phase II trial with dabrafenib and trametinib published in 2012.2 This modestly sized trial demonstrated statistically significant improvements in objective response rate and progression-free survival. Phase III trials were launched immediately to compare the efficacy of dabrafenib and trametinib to dabrafenib alone, in one study, and to vemurafenib, in another. Vemurafenib and cobimetinib were compared to vemurafenib alone in the third phase III trial. Only the dabrafenib/trametinib vs vemurafenib trial was designed with overall survival as the primary endpoint.
In all phase III trials, progression-free survival was improved with statistical significance. Curiously, the dabrafenib/trametinib vs dabrafenib phase III trial demonstrated a more modest impact on progression-free survival (hazard ratio [HR] = 0.75) than the dabrafenib/trametinib vs vemurafenib trial (HR = 0.56) or vemurafenib/cobimetinib vs vemurafenib trial (HR = 0.51).3-5
While overall survival appeared to be impacted to a comparable degree in the dabrafenib/trametinib vs dabrafenib and vemurafenib/cobimetinib vs vemurafenib trials, statistical significance sufficient to declare these interim overall survival analyses as positive was lacking. The dabrafenib/trametinib vs vemurafenib trial, on the other hand, was halted after the first interim analysis in light of an overall survival benefit of dabrafenib/trametinib sufficiently robust for the trial to be called definitively positive (HR = 0.69). Taken together, these trials provide clear and consistent evidence of the efficacy benefit for combined BRAF/MEK inhibition vs BRAF inhibitor monotherapy.
Toxicity and Cost Concerns
The race to develop effective combination targeted therapy regimens in various cancers aimed at producing durable control for a larger fraction of cancers for which single-agent oncogene-targeted therapy has been encumbered by concerns over increased toxicity and cost. At least for the BRAF/MEK inhibitor combinations, toxicity appears not to be a limit to the adoption of this approach in clinical practice.
When it was learned in the laboratory setting that BRAF inhibitors could activate the MAP kinase pathway in the context of RAS mutations, and RAS mutations were found in two-thirds of the cutaneous squamous cell carcinomas removed from patients receiving BRAF inhibitors in clinical trials,15 it was hoped that the addition of a MEK inhibitor might suppress this phenomenon. This hypothesis has been borne out, with all of the BRAF/MEK phase III trials demonstrating a statistically significant reduction in the rate of proliferative skin lesions, including squamous cell carcinomas.
While many have argued that these lesions are a relatively minor concern in the face of life-threatening metastatic melanoma, case reports have demonstrated the ability of this growth-promoting effect of BRAF inhibitors to underlie the emergence of other RAS-mutant malignancies. Thus, this benefit likely has real clinical significance as use of these therapies becomes more widespread and particularly if adjuvant therapy were demonstrated to be efficacious.
Closing Thoughts
With novel immunotherapies emerging in the same time frame as BRAF inhibitor–based treatment for metastatic melanoma, patient outcomes have been revolutionized in a short 5-year span. It is estimated that both BRAF/MEK combination therapy and PD-1–blocking antibodies produce 2-year survival rates of 50%.16 Considering that only 5 years ago, median overall survival in metastatic melanoma clinical trial populations was 6 to 9 months, this is a truly remarkable development.
Major challenges remain to identify which patients should receive BRAF inhibitor–based therapy or immunotherapy as first-line treatment and how these types of agents could be rationally combined. In parallel, triplet targeted therapy combinations are now being investigated in phase I trials aiming to overcome residual mechanisms of resistance to combined BRAF/MEK inhibition. Whether this steep trajectory of progress in melanoma can be maintained in the next few years remains to be seen, but optimism among melanoma care providers and patients has never been greater. ■
Disclosure: Dr. Flaherty has consulted for GlaxoSmithKline, Roche/Genentech, and Novartis.
References
1. Flaherty KT, Puzanov I, Kim KB, et al: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809-819, 2010.
2. Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694-1703, 2012.
3. 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 15:954-965, 2014.
4. Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. September 29, 2014 (early release online).
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9. Poulikakos PI, Persaud Y, Janakiraman M, et al: RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387-390, 2011.
10. Nazarian R, Shi H, Wang Q, et al: Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973-977, 2010.
11. Shi H, Moriceau G, Kong X, et al: Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724, 2012.
12. Wagle N, Van Allen EM, Treacy DJ, et al: MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 4:61-68, 2014.
13. 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 379:1893-1901, 2012.
14. Johnson DB, Flaherty KT, Weber JS, et al: Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. October 6, 2014 (early release online).
15. 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 366:207-215, 2012.
16. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014.
Dr. Flaherty is Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, Boston.
