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

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  1. Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity

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  2. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

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  3. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

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  4. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

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  5. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

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  1. The real-world outcome of metastatic melanoma: Unknown primary vs. known cutaneous

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  2. Arginase-1-based vaccination against the tumor microenvironment: the identification of an optimal T-cell epitope

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  3. Chimeric antigen receptor-T-cellebehandling

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  4. Real-World Impact of Immune Checkpoint Inhibitors in Metastatic Uveal Melanoma

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  • Paolo Antonio Ascierto
  • Pier Francesco Ferrucci
  • Rosalie Fisher
  • Michele Del Vecchio
  • Victoria Atkinson
  • Henrik Schmidt
  • Jacob Schachter
  • Paola Queirolo
  • Georgina V Long
  • Anna Maria Di Giacomo
  • Inge Marie Svane
  • Michal Lotem
  • Gil Bar-Sela
  • Felix Couture
  • Bijoyesh Mookerjee
  • Razi Ghori
  • Nageatte Ibrahim
  • Blanca Homet Moreno
  • Antoni Ribas
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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.

Original languageEnglish
JournalNature Medicine
Volume25
Issue number6
Pages (from-to)941-946
Number of pages6
ISSN1078-8956
DOIs
Publication statusPublished - Jun 2019

    Research areas

  • Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized/administration & dosage, Antineoplastic Agents, Immunological/administration & dosage, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Double-Blind Method, Female, Humans, Imidazoles/administration & dosage, Kaplan-Meier Estimate, MAP Kinase Kinase Kinases/antagonists & inhibitors, Male, Melanoma/drug therapy, Middle Aged, Mutation, Oximes/administration & dosage, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Progression-Free Survival, Protein Kinase Inhibitors/administration & dosage, Proto-Oncogene Proteins B-raf/antagonists & inhibitors, Pyridones/administration & dosage, Pyrimidinones/administration & dosage, Skin Neoplasms/drug therapy, Young Adult

ID: 57729068