Research in context
Evidence before this study
We searched PubMed up to March 8, 2015, for phase 1–3 clinical trials with the terms “combination”, “BRAF”, “MEK”, and “melanoma”. We identified 154 articles; of which, five were phase 1, 2, or 3 clinical trials of combined BRAF and MEK inhibitors. We searched the American Society for Clinical Oncology conference abstracts and identified three additional abstracts of clinical trials of combined BRAF and MEK inhibition that had not been published in full. BRAF and MEK inhibition decreased the number of hyperkeratotic skin toxic effects caused by paradoxical activation of the MAPK pathway, and delayed the onset of resistance compared with single-drug BRAF inhibition in preclinical studies of Val600Glu BRAF mutant models. This finding led to a phase 1/2 study of combined dabrafenib and trametinib in patients with Val600 BRAF mutation-positive metastatic melanoma. The phase 1 part of the study showed more responses, longer progression-free survival, and fewer cases of cutaneous squamous-cell carcinoma compared with historic controls treated with a single BRAF inhibitor. In the randomised phase 2 part of the study, the combination resulted in more responses (76% vs 54%, p=0·0264) and longer progression-free survival (9·4 months vs 5·8 months, HR 0·39, p<0·0001) than did monotherapy, with decreased oncogenic toxic effects (cutaneous squamous cell carcinoma and hyperkeratosis). Similarly, results of early-phase studies of other BRAF inhibitor and MEK inhibitor combinations showed more responses, a longer progression-free survival, and reduced incidence of cutaneous squamous-cell carcinoma, strongly supporting the rationale for a phase 3 trial of combined dabrafenib and trametinib versus BRAF inhibitor monotherapy.
Added value of this study
We report the final overall survival analysis of a double-blind, placebo-controlled, phase 3, randomised trial of the combination of dabrafenib and trametinib versus dabrafenib monotherapy. This study is also the most mature survival analysis for any phase 3 trial assessing the superiority of combined BRAF and MEK inhibition versus BRAF inhibition alone; thus we report the first median overall survival for any of the BRAF and MEK combinations from a phase 3 study (25·1 months). It adds weight to the open-label phase 3 trial of the same combination versus vemurafenib (the first BRAF inhibitor shown to improve overall survival compared with chemotherapy), which also resulted in improved overall survival (HR 0·69, p=0·0049) in favour of the combination.
Implications of all the available evidence
Our findings confirm the superiority of dabrafenib and trametinib in terms of the number of responses, duration of response, progression-free survival, and overall survival compared with the internationally approved BRAF inhibitors dabrafenib and vemurafenib. The combination reduced oncogenic adverse events caused by MAPK pathway reactivation. These data support the use of combined dabrafenib and trametinib as the standard targeted treatment for patients with Val600 BRAF mutation-positive metastatic melanoma.