Inhibition of BRAF and MEK in BRAF-mutant melanoma

Developments in the treatment of disseminated melanoma continue apace. In The Lancet, Georgina Long and colleagues 1 Long GV Stroyakovskiy D Gogas H et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015; (published online May 31.)http://dx.doi.org/10.1016/S0140-6736(15)60898-4 Google Scholar present long-term follow-up data from a large, multicentre, phase 3 clinical trial of patients with BRAF Val600Glu/Lys mutant melanoma, treated with the BRAF inhibitor dabrafenib plus either a placebo or the MEK inhibitor trametinib. The combination of BRAF and MEK inhibition is designed to inhibit the MAPK pathway vertically, with the hope of preventing or delaying resistance arising from reactivation of MEK–ERK signalling that typically occurs after single-agent BRAF inhibition. Combination of a BRAF and a MEK inhibitor limits therapeutic escape in vitro and in animal models. 2 Fedorenko IV Gibney GT Sondak VK Smalley KS Beyond BRAF: where next for melanoma therapy?. Br J Cancer. 2015; 112: 217-226 Crossref PubMed Scopus (94) Google Scholar Reactivation of the MAPK pathway is a common BRAF inhibitor resistance mechanism, present in up to 80% of post-relapse specimens. 2 Fedorenko IV Gibney GT Sondak VK Smalley KS Beyond BRAF: where next for melanoma therapy?. Br J Cancer. 2015; 112: 217-226 Crossref PubMed Scopus (94) Google Scholar Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trialThe improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. Full-Text PDF