BRAF ± MEK inhibition following pembrolizumab (pembro) in KEYNOTE-006

Abstract

The efficacy of BRAF+MEK inhibition as first‐line therapy for BRAFV600‐mutant melanoma is well established. In the KEYNOTE‐006 study of pembro 10 mg/kg Q2W or Q3W versus ipilimumab 3 mg/kg Q3W for patients (pts) with advanced melanoma (NCT01866319), ORR in the pooled pembro arms was 38% for BRAFV600 wild type (n = 355) and 32% for BRAFV600 mutant (n = 195) disease. We assessed the activity of BRAF ± MEK inhibition as the first subsequent therapy following pembro in KEYNOTE‐006. As of Nov 3, 2016, 30 pts received BRAF+MEK inhibition and 29 pts received BRAF inhibition alone as their first subsequent therapy after pembro. All 59 pts had BRAFV600‐mutant disease, 68% had M1c disease, 15% had elevated LDH, and 5% had brain metastases at study baseline; 36% of pts received BRAF ± MEK inhibitors before study entry. Pts received pembro for a median 12.3 week (range, 0.1‐100.3) with best re‐sponse (central RECIST v1.1) of PR in 14%, SD in 14%, nonCR/nonPD in 3%, PD in 63%, and nonevaluable/unknown in 7%. Median interval between pembro and BRAF ± MEK inhibition was 3.3 week (range, 0.1‐65.7). Median duration of subsequent BRAF ± MEK inhibition was 28.3 week (range, 1.6‐136.1). Reported ORR for BRAF ± MEK inhibition was 31% overall, 30% for BRAF+MEK and 31% for BRAF alone; ORR was 10% in pts with prior BRAF ± MEK and 42% in pts without. Best response to subsequent BRAF ± MEK inhibition was CR in 8%, PR in 22%, SD in 34%, PD in 29%, and nonevaluable/unknown in 7%; subsequent PD occurred in 0% of CRs, 54% of PRs, and 70% of SDs. 38 of the 59 pts had died, and median OS from randomization was 17.9 months (95% CI, 14.9‐31.2). Although ORR in this post‐hoc, exploratory analysis is less than that observed in phase 3 trials of first‐line BRAF ± MEK inhibition, BRAF ± MEK inhibition appears to have antitumor activity following pembro in pts with advanced BRAFV600‐mutant melanoma, particularly in those without prior BRAF ± MEK therapy.