BRAF and MEK inhibition in melanoma

Introduction: Selective inhibition of the MAPK pathway with either BRAF or MEK inhibition has emerged as a key component for the treatment of BRAF-mutant metastatic melanoma. New evidence suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival, while potentially attenuating some of the serious adverse events observed with monotherapy. Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF (vemurafenib and dabrafenib) and MEK (trametinib) inhibitors as well as the available data on BRAF inhibitor + MEK inhibitor combination therapy (dabrafenib + trametinib and vemurafenib + cobimetinib). The efficacy, safety and toxicity data are discussed from Phase I, Phase II and Phase III trials of these drugs. Expert opinion: Combination therapy with the BRAF and MEK inhibitors improves response rates and progression-free survival in patients with BRAF-mutant metastatic melanoma. Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma, are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for patients compared to single agent BRAF inhibitors.