Loading...
At present, two selective BRAF inhibitors (dabrafenib and vemurafenib) and one MEK inhibitor (trametinib) are FDA-approved for treating stage IV BRAFV600E-mutated metastatic melanoma. Single-agent dabrafenib but not vemurafenib has been tested against combination dabrafenib/trametinib. Vemurafenib monotherapy is in current use; these investigators studied its efficacy relative to combination dabrafenib/trametinib.
A total of 704 patients were randomized to receive either oral vemurafenib (960 mg twice daily) or dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) as first-line therapy; Ten percent of patients in each group had BRAFV600K mutation as opposed to BRAFV600E mutations. Median follow-up was 11 months in combined-therapy recipients and 10 months in vemurafenib recipients; there were 100 deaths in combined-therapy patients (28%) versus 122 in vemurafenib recipients (35%), a significant difference. Median progression-free survival was also significantly longer in the combination-therapy group (11.4 months vs. 7.3 months). Cutaneous neoplasms occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.
Robert C et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2014 Nov 16; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1412690)
Comment
This finding is not surprising, given that multiple previous reports showed added benefit with combined BRAF+MEK inhibition versus single-agent BRAF inhibition. A direct head-on comparison with vemurafenib was important, as was the demonstrated benefit in overall survival and not just progression-free survival. As previously observed, squamous proliferations were largely suppressed with combination treatment. At this point, combination BRAF+MEK inhibition rather than single-drug treatment is quickly emerging as the new standard for BRAFV600-mutated melanoma.