Michael Postow, MD
The landscape of treatment options for patients with advanced and/or metastatic melanoma continues to expand, with immunotherapies and targeted therapies, as well as combinations thereof, gaining approval in recent years. As such, it is becoming increasingly important to understand the patient-specific oncogenic drivers as a means of selecting treatments. The current National Comprehensive Cancer Network (NCCN) guidance recognizes the importance of BRAF
testing for patients with metastatic disease.1
As clinical experience grows with new agents, combinations, and sequences of therapy, the use of molecular profiling in metastatic melanoma is likely to become an essential means of choosing among treatment options.
Evolution of Immunotherapies
Patients with metastatic or unresectable melanoma are now candidates for first-line systemic therapy with anti-PD-1 receptor antibodies (category 1 recommendation) as monotherapy (pembrolizumab and nivolumab), but targeted therapies are preferred in BRAF
-mutated disease, in cases where an early response is clinically desirable.1 Other options include the nivolumab/ ipilimumab (anti-CTLA-4) combination.1
Recent phase III results reported in The New England Journal of Medicine
demonstrated that the use of nivolumab, an anti-PD-1 agent, either alone or in combination with ipilimumab, an anti– CTLA-4 agent, significantly improved median progression-free survival (PFS) compared with ipilimumab alone.2
As a result, a range of treatment options now exists for patients with BRAF
Evolution of BRAF-Targeted Therapy
Current NCCN guidance recommends considering targeted therapies for patients with BRAF
-mutant melanoma with symptomatic disease, or who progress on immunotherapies.1
Vemurafenib was the first targeted therapy to become available for patients with metastatic melanoma, and was shown to improve overall and progression-free survival (PFS) over conventional chemotherapy (dacarbazine), the standard of care at the time.3 Vemurafenib is currently approved for use in patients with BRAF
-mutation–positive melanoma, as determined by an FDA-approved test (Cobas).4
Subsequently, a second BRAF inhibitor dabrafenib, became available for use after it was shown to also improve PFS compared with dacarbazine. 5
Adverse events (AEs) associated with these BRAF
-targeted therapies include skin toxicities, which were observed in a sizable proportion of patients.3,5-7
It now appears that these toxicities stemmed from a paradoxical activation of the MAP kinase pathway by these agents, and these observations, in addition to patients’ propensity to develop resistance to monotherapy, have more recently paved the way for their use in combination with MEK-directed agents in patients with BRAF
-mutation– positive disease.8-11
Recent phase III trials have established the clinical feasibility of using BRAF inhibitors and MEK inhibitors in combination, and the FDA has approved two such regimens for clinical use based on late-stage clinical trial results. In mid-November, the FDA granted full approval to the combination of dabrafenib and trametinib for patients with unresectable or metastatic BRAF
-mutated melanoma, based on an extension in median overall survival (OS) from two phase III studies. The agency had given the regimen a green light on an accelerated approval basis pending confirmatory trials in January 2014.
In the COMBI-v trial, median OS was extended by 7.6 months with dabrafenib and trametinib compared with single-agent vemurafenib (25.6 months vs 18 months, respectively).10 In the COMBI-d trial, median OS was improved by 6.4 months with a combination of the two drugs compared with dabrafenib alone (25.1 months vs 18.7 months, respectively).11
Moreover, across both studies, the combination was found to induce fewer AEs compared with either agent alone.
Also in November, the FDA approved the combination of vemurafenib and cobimetinib as a treatment for patients with BRAF
-positive metastatic or unresectable melanoma, based on an extension in progression-free survival (PFS) in the phase III coBRIM study.
In updated findings presented at the 2015 Society for Melanoma Research Congress, treatment with the combination of vemurafenib and cobimetinib improved OS by 4.9 months compared with vemurafenib alone for patients with BRAF
mutation-positive advanced melanoma.12