Dabrafenib plus Trametinib vs. Dabrafenib Alone for BRAF-Mutant Melanoma

These results support a new standard of care in molecular therapy.

Several randomized trials have demonstrated short-term survival benefits from combination BRAF+MEK inhibition therapy in patients with BRAF-mutant melanoma. MEK pathway reactivation is a mechanism of BRAF-inhibitor resistance, so combined therapy is hoped to prevent or delay resistance. The long-term overall survival effects of the combination regimen have not been established. Investigators of a recent large, multicenter (113 sites; 14 countries) phase III study now report an additional 17 months of follow-up data on combination dabrafenib+trametinib therapy.

A total of 423 patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma were randomized to receive the combined regimen or dabrafenib plus placebo. Median overall survival was 25.1 months (95% confidence interval, 19.2–not reached) in the dabrafenib+trametinib group, versus 18.7 months (15.2–23.7) in the dabrafenib-only group (hazard ratio, 0.71; 95% CI, 0.55–0.92; P=0.0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib+trametinib group versus 68% and 42%, respectively, in the dabrafenib-only group.

Comment

These results firmly establish combination dabrafenib+trametinib as the standard of molecular therapy care. Despite earlier hopes that concurrent MEK inhibition would completely abrogate resistance, such does not seem to be the case. Other multitarget molecular cocktails are in the works, but a role for immune checkpoint therapies must be considered, given the recent impressive results with anti-PD1 treatments. Because it will be important to test regimens in BRAF-inhibitor naive patients, editorialists urge clinicians to refer such patients to research and not only those who have failed to respond to BRAF- and MEK-inhibitor treatment.

Reviewing Author

Hensin Tsao, MD, PhD

Disclosures

Consultant / advisory board Lubax; WorldCare Clinical

EquityLubax

Grant / Research support NIH; Department of Defense; American Skin Association; Piramal

Editorial boardsBritish Journal of Dermatology; Journal of the American Academy of Dermatology; Journal of Investigative Dermatology

Leadership positions in professional societies American Academy of Dermatology (Chair, Skin Cancer and Melanoma Committee); American Board of Dermatology (Director)