Research in context
Evidence before this study
We searched PubMed up until Sept 30, 2015, with the terms “clinical trials”, “advanced melanoma”, “BRAF inhibitor”, and “MEK inhibitor”. We also searched conference abstracts from the American Society of Clinical Oncology and the European Society of Medical Oncology with the same terms. The results showed that, in addition to the combination of vemurafenib and cobimetinib, BRAF and MEK inhibitor combinations of dabrafenib and trametinib, LGX818 and MEK162 (encorafenib and binimetinib), have been or are being assessed in patients with advanced BRAFV600-mutant melanoma. Data from two phase 3 studies have shown a benefit for the trametinib and dabrafenib combination, whereas other combinations resulted in promising activity in early-phase trials.
Added value of this study
We report the protocol-specified overall survival analysis of a double-blind, multicentre, placebo-controlled phase 3 study assessing the efficacy and safety of cobimetinib and vemurafenib compared with placebo and vemurafenib in previously untreated patients with BRAFV600 mutation-positive unresectable stage IIIC or IV melanoma. Effectiveness of the combination of cobimetinib and vemurafenib was superior to that of vemurafenib plus placebo for all efficacy endpoints and across a wide range of patient baseline characteristics, including in patients with normal baseline lactate dehydrogenase concentrations. To our knowledge, this is the first phase 3 comparative trial to do biomarker analyses to study the effect of baseline values of Ki67, pERK, and pS6 on median overall survival in both treatment groups.
Implications of all the available evidence
These data confirm the clear and definitive clinical benefit of the addition of cobimetinib to vemurafenib in patients with advanced BRAFV600-mutant melanoma and support the use of the combination as a standard targeted therapy for first-line treatment in this population.