Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma
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Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. / Ascierto, Paolo Antonio; Ferrucci, Pier Francesco; Fisher, Rosalie; Del Vecchio, Michele; Atkinson, Victoria; Schmidt, Henrik; Schachter, Jacob; Queirolo, Paola; Long, Georgina V; Di Giacomo, Anna Maria; Svane, Inge Marie; Lotem, Michal; Bar-Sela, Gil; Couture, Felix; Mookerjee, Bijoyesh; Ghori, Razi; Ibrahim, Nageatte; Moreno, Blanca Homet; Ribas, Antoni.
I: Nature Medicine, Bind 25, Nr. 6, 2019, s. 941-946.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2019
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
VL - 25
SP - 941
EP - 946
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 6
ER -
ID: 231902004