Are we there yet? Prolonged MAPK inhibition in BRAFV600-mutant melanoma

The years 2011–16 represent a watershed era in melanoma history. 1 Merlino G Herlyn M Fisher DE et al. The state of melanoma: challenges and opportunities. Pigment Cell Melanoma Res. 2016; 29: 404-416 Crossref PubMed Scopus (69) Google Scholar This period has seen the approval of several molecularly targeted or immunotherapy drugs that meaningfully improve outcomes for patients with unresectable or metastatic melanoma. Targeting the MAP kinase (MAPK) pathway through combined BRAF and MEK inhibition has been very successful, yet the eventual development of resistance through reactivation of MAPK signalling is nearly inevitable. 2 Paraiso KH Fedorenko IV Cantini LP et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010; 102: 1724-1730 Crossref PubMed Scopus (253) Google Scholar In The Lancet Oncology, Paolo Ascierto and colleagues report the extended follow-up results of the coBRIM phase 3 trial evaluating the addition of the MEK inhibitor cobimetinib to the BRAF inhibitor vemurafenib in patients with previously untreated BRAFV600-mutant metastatic melanoma. 3 Ascierto PA McArthur GA Dréno B et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016; (published online July 29.)http://dx.doi.org/10.1016/S1470-2045(16)30122-X Google Scholar With longer follow-up (median 14·2 months [IQR 8·5–17·3]) than the initial report, the results confirm a significant improvement in progression-free survival for vemurafenib plus cobimetinib compared with vemurafenib plus placebo (12·3 months vs 7·2 months; HR 0·58 [95% CI 0·46–0·72], p<0·0001), which also translated into longer overall survival in the combination therapy group (22·3 months vs 17·4 months; HR 0·70 [95% CI 0·55–0·90], p=0·005). Exploratory biomarker analyses did not show an association with survival, and we remain woefully unable to predict for individual patients with BRAFV600-mutant melanoma what the magnitude and duration of response to targeted therapy will be. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trialThese data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAFV600-mutant melanoma. Full-Text PDF