Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma: Nature Medicine

P.A. Ascierto, P.F. Ferrucci, R. Fisher, M. Del Vecchio, V. Atkinson, H. Schmidt, J. Schachter, P. Queirolo, G.V. Long, A.M. Di Giacomo, I.M. Svane, M. Lotem, G. Bar-Sela, F. Couture, B. Mookerjee, R. Ghori, N. Ibrahim, B.H. Moreno, A. Ribas

Research output: Contribution to journalArticlepeer-review

Abstract

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial (NCT02130466), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group—16.0 months—compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1–22.1) and 12.5 months (95% confidence interval, 6.0–14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3–5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Original languageEnglish
Pages (from-to)941-946
Number of pages6
JournalNat. Med.
Volume25
Issue number6
DOIs
Publication statusPublished - 2019

Keywords

  • alanine aminotransferase
  • aspartate aminotransferase
  • B Raf kinase
  • dabrafenib
  • gamma glutamyltransferase
  • pembrolizumab
  • trametinib
  • antineoplastic agent
  • BRAF protein, human
  • imidazole derivative
  • immunological antineoplastic agent
  • mitogen activated protein kinase kinase kinase
  • monoclonal antibody
  • oxime
  • PDCD1 protein, human
  • programmed death 1 receptor
  • protein kinase inhibitor
  • pyridone derivative
  • pyrimidinone derivative
  • adult
  • advanced cancer
  • adverse event
  • aminotransferase blood level
  • aspartate aminotransferase level
  • cancer combination chemotherapy
  • cancer survival
  • controlled study
  • diarrhea
  • double blind procedure
  • fatigue
  • fever
  • gene mutation
  • human
  • hypertension
  • hyperthyroidism
  • hypertransaminasemia
  • hypothyroidism
  • Letter
  • major clinical study
  • melanoma
  • nausea
  • neutropenia
  • overall survival
  • phase 2 clinical trial
  • pneumonia
  • priority journal
  • progression free survival
  • randomized controlled trial
  • rash
  • skin disease
  • uveitis
  • adolescent
  • aged
  • antagonists and inhibitors
  • clinical trial
  • female
  • genetics
  • Kaplan Meier method
  • male
  • middle aged
  • multicenter study
  • mutation
  • pathology
  • skin tumor
  • very elderly
  • young adult
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • Antineoplastic Combined Chemotherapy Protocols
  • Double-Blind Method
  • Female
  • Humans
  • Imidazoles
  • Kaplan-Meier Estimate
  • Male
  • MAP Kinase Kinase Kinases
  • Melanoma
  • Middle Aged
  • Mutation
  • Oximes
  • Programmed Cell Death 1 Receptor
  • Progression-Free Survival
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Pyridones
  • Pyrimidinones
  • Skin Neoplasms
  • Young Adult

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