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

TY - JOUR

T1 - Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma

AU - Ascierto, Paolo Antonio

AU - Ferrucci, Pier Francesco

AU - Fisher, Rosalie

AU - Del Vecchio, Michele

AU - Atkinson, Victoria

AU - Schmidt, Henrik

AU - Schachter, Jacob

AU - Queirolo, Paola

AU - Long, Georgina V

AU - Di Giacomo, Anna Maria

AU - Svane, Inge Marie

AU - Lotem, Michal

AU - Bar-Sela, Gil

AU - Couture, Felix

AU - Mookerjee, Bijoyesh

AU - Ghori, Razi

AU - Ibrahim, Nageatte

AU - Moreno, Blanca Homet

AU - Ribas, Antoni

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal, Humanized/administration & dosage

KW - Antineoplastic Agents, Immunological/administration & dosage

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Double-Blind Method

KW - Female

KW - Humans

KW - Imidazoles/administration & dosage

KW - Kaplan-Meier Estimate

KW - MAP Kinase Kinase Kinases/antagonists & inhibitors

KW - Male

KW - Melanoma/drug therapy

KW - Middle Aged

KW - Mutation

KW - Oximes/administration & dosage

KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors

KW - Progression-Free Survival

KW - Protein Kinase Inhibitors/administration & dosage

KW - Proto-Oncogene Proteins B-raf/antagonists & inhibitors

KW - Pyridones/administration & dosage

KW - Pyrimidinones/administration & dosage

KW - Skin Neoplasms/drug therapy

KW - Young Adult

U2 - 10.1038/s41591-019-0448-9

DO - 10.1038/s41591-019-0448-9

M3 - Journal article

C2 - 31171878

SN - 1078-8956

VL - 25

SP - 941

EP - 946

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -