KEYNOTE-022 Part 3: Phase II randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma

Background: Pembro + D + T had promising antitumor activity and acceptable tolerability in phase 1 of KEYNOTE-022 (NCT02130466). Methods: In the double-blind phase 2 part of KEYNOTE-022, pts with treatment (tx)-naive BRAFV600E/K-mutant stage III/IV melanoma were randomly assigned (stratified by ECOG PS [0/1)]; LDH level [>1.1 vs ≤ 1.1× ULN]) to pembro 2 mg/kg Q3W + D 150 mg BID + T 2 mg QD or PBO + D + T. Strata with ECOG PS 1 and either LDH level were combined due to small numbers. Primary end point was PFS. Significance requirements to reject null hypothesis at 1-sided 0.025 type I error: ∼74 PFS events for 80% power; observed HR ≤ 0.62. Additional end points included ORR, DOR, TTR, and OS. Data cutoff: Feb 15, 2018. Results: Of 60 pts in each arm, most baseline characteristics were balanced (stage IV disease, 98% in pembro + D + T vs 95% in PBO + D + T; ECOG PS 0, 80% both; LDH >1.1× ULN, 45% vs 43%). Median follow-up for both arms was 9.6 mo (range 2.7-23.4). 67% vs 70% received ≥12 mo tx. Median PFS was 16.0 mo (95% CI 8.6-21.5) with pembro + D + T vs 10.3 mo (95% CI 7.0-15.6) with PBO + D + T; HR, 0.66; P = 0.04287; 12-mo PFS rates were 59% vs 45%. ORR was 63% vs 72%; CR rates were 18% vs 13%. Median TTR was 2.8 mo in each arm; median DOR was 18.7 mo (range 1.9+ to 22.1) vs 12.5 (2.1-19.5+). More patients (60%) on pembro + D + T had responses lasting ≥18 mo vs PBO + D + T (28%). OS rates at 12 mo were 80% vs 73%. Any grade (G) treatment-related AEs (TRAEs) occurred in 95% vs 93% and G3-5 TRAEs occurred in 58% vs 27% of pts. G3-5 TRAEs occurring in ≥ 5% of pts were pyrexia (10% vs 3%), increased ALT (7% vs 5%), increased AST (8% vs 5%), increased GGT (7% vs 5%), rash (5% vs 2%), and neutropenia (2% vs 5%). 40% vs 20% of pts discontinued any of the 3 study tx due to TRAEs, and 1 pt died due to a TRAE (pneumonitis) in the pembro + D + T arm. Immune-mediated AEs occurred in 43% vs 13% of pts, most commonly pneumonitis (15% vs 2%), hypothyroidism (8% vs 2%), skin disorders (7% vs 2%), hyperthyroidism (5% vs 0%), and uveitis (5% vs 3%); most resolved with tx discontinuation/modification. Conclusions: Pembro + D + T vs PBO + D + T demonstrated numerically longer PFS and DOR and a higher rate of G3-5 TRAEs in pts with tx-naive BRAFV600E/K-mutant advanced melanoma. Clinical trial identification: NCT02130466. Editorial acknowledgement: Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: P.A. Ascierto: Advisory board member: BMS, Roche-Genentech, MSD, Array, Novartis, Amgen, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, Medimmune, Syndax, AstraZeneca; Research funding: BMS, Roche-Genentech, Array. P.F. Ferrucci: Advisory board member: BMS, Novartis, MSD; Research funding: BMS, MSD; Honoraria, travel expenses, accommodations: BMS, Novartis, MSD, Roche. R. Stephens: Honoraria, travel expenses: MSD NZ. M. Del Vecchio: Consultant, advisor, research funds: Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline, Merck Sharp and Dohme. V. Atkinson: Advisory board member: BMS, MSD, Novartis, Merck Serono, Pierre Fabre; Speakers’ bureau: BMS, MSD, Novartis, Roche; Honoraria: BMS, MSD, Novartis; Travel expenses: BMS, MSD. H. Schmidt: Advisory board member: BMS, MSD, Incyte, Roche; Speakers’ bureau: BMS, Novartis; Research funding: MSD; BMS. J. Schachter: Honoraria, consultant/advisory, travel, accomodations, expenses: BMS, MSD. P. Queirolo: Advisory board member, speakers' bureau, honoraria, travel expenses, accommodations: BMS, Roche, Novartis, MSD. G.V. Long, A.M. Di Giacomo: Advisory board member: Incyte, GSK, Pierre Fabre; Honoraria: BMS, Roche, MSD; Travel expenses, including accommodations: BMS, Roche. I. Svane: Honoraria/Consulting fees: Roche, Novartis, Merck, MSD, Celgene, Incyte, Pfizer, BMS, AstraZeneca, TILT Bio, IO Biotech; Stock (co-founder): IO Biotech. M. Lotem: Advisory board member: Merck; Honoraria: Merck, BMS; Travel expenses, accommodations: Merck, BMS, Novartis. G. Bar-Sela: Research funding: Merck. B.P. Mookerjee: Employee: Novartis; Stock: Novartis, GSK, AstraZeneca. R. Ghori, N. Ibrahim, B. Homet Moreno: Employee: Merck & Co., Inc. A. Ribas: Stock ownership: Lutris, PACT, Tango; Advisory board member: Advaxis, Arcus, BioncoTech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Rgenix; Honoraria: Amgen, BMS, Chugai, Genentech, Merck, Novartis, Roche. All other authors have declared no conflicts of interest.

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