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

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  • Pier Francesco Ferrucci, IRCCS Istituto Europeo di Oncologia - Milano
  • ,
  • Anna Maria Di Giacomo, University of Siena
  • ,
  • Michele Del Vecchio, IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
  • ,
  • Victoria Atkinson, University of Queensland
  • ,
  • Henrik Schmidt
  • Jacob Schachter, Sheba Medical Center at Tel Hashomer
  • ,
  • Paola Queirolo, IRCCS Istituto Europeo di Oncologia - Milano
  • ,
  • Georgina V. Long, University of Sydney, Mater Hospital
  • ,
  • Rosalie Stephens, Auckland City Hospital
  • ,
  • Inge Marie Svane, University of Copenhagen
  • ,
  • Michal Lotem, Hadassah University Medical Centre
  • ,
  • Mahmoud Abu-Amna, Rambam Health Care Center
  • ,
  • Eduard Gasal, Novartis
  • ,
  • Razi Ghori, Merck
  • ,
  • Scott J. Diede, Merck
  • ,
  • Elizabeth S. Croydon, Merck
  • ,
  • Antoni Ribas, University of California at Los Angeles
  • ,
  • Paolo Antonio Ascierto, IRCCS Istituto nazionale tumori Fondazione Giovanni Pascale - Napoli

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.

Original languageEnglish
Article numbere001806
JournalJournal for immunotherapy of cancer
Volume8
Issue2
ISSN2051-1426
DOIs
Publication statusPublished - Dec 2020

    Research areas

  • combination, drug therapy, immunotherapy, melanoma, programmed cell death 1 receptor

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