This phase 3 study showed an improvement in the response rate and in progression-free survival when cobimetinib was added to vemurafenib. Together with the results of a phase 3 trial comparing dabrafenib plus trametinib with dabrafenib alone,19 these findings provide clear evidence of the benefit of combined MEK and BRAF inhibition. The data combining BRAF and MEK inhibitor–targeted therapies need to be put in context with the rapidly evolving melanoma-treatment landscape — namely, the development of immunotherapies that are based on checkpoint blockade with ipilimumab or anti–programmed death 1 antibodies. Evidence suggests that these agents can lead to durable tumor responses in patients with metastatic melanoma, albeit with lower response rates than have been observed with BRAF and MEK inhibition.
The primary end point of the hazard ratio for the risk of progression or death that we report for vemurafenib plus cobimetinib, as compared with vemurafenib alone, is significant. The data from the prespecified interim analysis of overall survival we report here are immature, reflecting analysis at the time of the planned analysis of progression-free survival, and they do not cross the boundary prespecified in the statistical analysis plan. Nevertheless, these early data are encouraging, although mature data are needed before definitive conclusions can be drawn. The consistency between both primary and secondary end points and subgroups is a strength of the current study, as was the performance of the control group, which was broadly consistent with prior randomized trials of BRAF inhibitors in both the response rate and median progression-free survival. It is possible that the intermittent dosing regimen of cobimetinib, resulting from the definition of the maximum tolerated dose in phase 1 testing, might have an effect on the outcomes of the combination with vemurafenib: preclinical data suggest that the intermittent blockade of oncogenic BRAF signaling might delay the development of acquired resistance.
Read full article: Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma (https://www.nejm.org/doi/full/10.1056/NEJMoa1408868#t=articleTop)