The combination of vemurafenib and cobimetinib in advanced melanoma

Introduction: Advanced melanoma with a BRAF V600 mutation responds to treatment with BRAF inhibitors such as vemurafenib, with great improvement in tumour response and patient survival. Despite early and often dramatic responses, resistance to vemurafenib develops. Concurrent inhibition of a downstream protein, MEK, also involved in the MAPK oncogenic signalling pathway, defers development of resistance. The MEK inhibitor cobimetinib has been successfully and safely combined with vemurafenib, further improving response rate and survival when compared to vemurafenib monotherapy.Areas covered: This article covers the mechanism of action of both vemurafenib and cobimetinib, in addition to describing results from the key Phase I and Phase III studies which led to registration of the combination in the US and Europe as a therapeutic option for advanced BRAF mutant melanoma. The safety profile of these agents is also discussed in detail, including similarities with and differences from the competitor compounds dabrafenib and trametinib.Expert opinion: Vemurafenib in combination with cobimetinib provides an alternative BRAF/MEK blockade. The combination is tolerable, safe and effective and results in fewer skin toxicities than vemurafenib monotherapy.