Clinical StudiesSequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF InhibitionJohnson, Douglas B.*; Pectasides, Eirini†,‡; Feld, Emily*; Ye, Fei*; Zhao, Shilin*; Johnpulle, Romany*; Merritt, Ryan§; McDermott, David F.§; Puzanov, Igor*; Lawrence, Donald§; Sosman, Jeffrey A.*; Buchbinder, Elizabeth‡; Sullivan, Ryan J.§ Author Information *Vanderbilt University Medical Center, Nashville, TN †Beth Israel Deaconess Medical Center ‡Dana-Farber Cancer Institute §Massachusetts General Hospital, Boston, MA Supported by K12 CA 0906525 (D.B.J.). Reprints: Douglas B. Johnson, 777 PRB, 2220 Pierce Ave, Nashville, TN 37232. (e-mail: [email protected]). Journal of Immunotherapy 40(1):p 31-35, January 2017. | DOI: 10.1097/CJI.0000000000000148 Buy Metrics Abstract Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAFV600-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, BRAFV600-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 BRAFV600-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. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.