KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF -mutant melanoma.

Background: In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.
Methods: The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAF ^V600E/K -mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.
Results: Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.
Conclusion: In BRAF ^V600E/K -mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
Competing Interests: Competing interests: PFF has received personal fees from Novartis, Roche, Bristol-Myers Squibb, Pierre Fabre, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Kenilworth, New Jersey, USA (MSD). AMDG reports other from MSD during the conduct of the study; reports other from Incyte, GlaxoSmithKline, Pierre Fabre, and Sanofi outside the submitted work; and has served as an advisor and consultant for MSD, Incyte, GlaxoSmithKline, Pierre Fabre, and Sanofi. MDV has received personal fees from Novartis, MSD, and BMS outside the submitted work and has served as an advisor and consultant for MSD, BMS, Novartis, Pierre Fabre and Sanofi. VA has received personal fees and travel support from Bristol-Myers Squibb; personal fees from MSD, Merck Serono, Novartis, Pierre Fabre, Roche and Nektar; and travel support from OncoSec Medical, during the conduct of the study. HS received a research grant and personal fees from MSD and has received personal fees from Bristol-Myers Squibb, Incyte, Novartis, and Pierre Fabre outside the submitted work. PQ has received personal fees from Roche, Novartis, Bristol-Myers Squibb, MSD, Sanofi, and Pierre Fabre. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., MSD, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDx B.V. RS reports personal fees from MSD New Zealand, outside the submitted work. IMS reports other (trial expenses) from MSD. IMS has received other funds from MSD during the conduct of the study. EG is an employee and stockholder of Novartis. RG is an employee of MSD. SJD is an employee and stockholder of MSD. ESC was an employee of MSD at the time of this study. AR has received personal fees from Amgen, Chugai, Novartis, Genentech-Roche, Sanofi, and Merck and serves as an advisor for, holds stock in, and has received personal fees from Arcus, Bioncotech, Compugen, CytomX, Five Prime, RAPT Therapeutics, Merus, Rgenix, PACT Pharma, and Tango Therapeutics outside the submitted work. PAA has received grants and personal fees from Bristol-Myers Squib, Roche-Genentech, and Array BioPharma; personal fees and other from MSD; and personal fees from Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, NewLink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, and Boehringer Ingelheim. JS, ML, and MA-A report no competing interests.
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