Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition

Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF(V600)-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF(V600)-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n = 56) versus those that received BRAF +/- MEK inhibitors (BRAFi) first (n = 58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P = 0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD 1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited > 6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (< 6 mo) on BRAFi (34% vs. 15%, P = 0.04). We conclude that either BRAFi or anti-PD-1 may be effective regardless of treatment sequence in patients with BRAF(V600)-mutant melanoma, but clinical outcomes to front-line therapy are superior. In addition, we suggest a shared responder phenotype between BRAFi and anti-PD-1.