MADRID – More complete blockade of the MAP kinase pathway with both a BRAF and MEK inhibitor decreased the risk of death by one-third among patients with advanced BRAF mutation–positive melanoma in the phase III COMBI-v study.
After a median follow-up of 10-11 months, the primary endpoint of overall survival was 17.2 months with the BRAF inhibitor vemurafenib (Zelboraf) alone, but had not been reached with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) (hazard ratio, 0.69; P = .005).
Patrice Wendling/Frontline Medical News
Dr. Caroline Robert
“This combination has met all the endpoints that were looked for, and I’d like to remind you that we compared this combination to an already very active drug,” study author Dr. Caroline Robert, head of dermatology at the Institut Gustave Roussy in Paris, said during a presidential session at the European Society for Medical Oncology Congress.
Patients in the combination arm had significantly better median progression-free survival than those given vemurafenib monotherapy (11.4 vs. 7.3 months; HR, 0.56; P < .001), as well as higher response rates (64% vs. 51%; P < .001), more complete responses (13% vs. 8%), and a longer duration of response (13.8 vs. 7.5 months).
COMBI-v was stopped early for efficacy at the interim analysis, which de facto became the final overall survival analysis presented by Dr. Robert.
The study evenly randomized 704 patients with stage IIIC or IV BRAF V600E or V600K mutation–positive melanoma to first-line therapy with twice-daily dabrafenib 150 mg plus daily trametinib 2 mg or twice-daily vemurafenib 960 mg.
The study sponsor, GlaxoSmithKline, gained accelerated approval in the United States in January 2014 for use of combination dabrafenib and trametinib in unresectable BRAF V600E or V600K mutation–positive melanoma based on positive response data.
The strategy of up-front BRAF and MEK inhibition in BRAF-mutant unresectable disease was supported by data presented in the same session from the coBRIM study, where treatment with vemurafenib and the investigational MEK inhibitor cobimetinib improved progression-free survival, response rates, and overall survival, although the overall survival data are immature. Listen to our interview with coBRIM study author Dr. Grant McArthur.
Dr. Christian Blank, from the Netherlands Cancer Institute in Amsterdam, who was invited to discuss both studies, commented that the combinations used in COMBI-v and coBRIM had similar toxicity to that of single-agent treatment, and that if mature data confirm the presented observations, combined BRAF and MEK inhibition is the new standard therapy for patients with BRAF V600 melanoma.
In COMBI-v, patients receiving dabrafenib plus trametinib, as compared with vemurafenib alone, had more pyrexia (53% vs. 21%), chills (31% vs. 8%), and decreases in ejection fraction (8% vs. 0%), although the latter was easily reversible without sequelae, Dr. Robert stressed. The addition of a MEK inhibitor, however, reduced BRAF inhibitor–related adverse skin events such as cutaneous squamous cell carcinoma and keratoacanthoma (1% vs. 18%), as well as photosensitivity (4% vs. 36%).
GlaxoSmithKline funded the study. Dr. Robert reported serving as a consultant to GlaxoSmithKline, Roche, Bristol-Myers Squibb, Amgen, Novartis, and Merck. Dr. Blank disclosed an advisory role with GSK, Roche, BMS, MSD, and Novartis, honoraria from GSK, Roche, BMS, and MSD, and a research grant from Novartis.