title: Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition.
abstract: Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-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-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-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.
authors.affiliation: *Vanderbilt University Medical Center, Nashville, TN †Beth Israel Deaconess Medical Center ‡Dana-Farber Cancer Institute §Massachusetts General Hospital, Boston, MA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.forename: Eirini
authors.initials: E
authors.lastname: Pectasides
authors.forename: Emily
authors.initials: E
authors.lastname: Feld
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhao
authors.forename: Romany
authors.initials: R
authors.lastname: Johnpulle
authors.forename: Ryan
authors.initials: R
authors.lastname: Merritt
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Donald
authors.initials: D
authors.lastname: Lawrence
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buchbinder
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
mesh_terms: D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D015331:Cohort Studies; D065187:Controlled Before-After Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000074324:Ipilimumab / Q000627:therapeutic use*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases