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

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

doi:10.1038/s41591-019-0448-9

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

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

Institut for Klinisk Medicin

107 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Medicine
Vol/bind	25
Udgave nummer	6
Sider (fra-til)	941-946
Antal sider	6
ISSN	1078-8956
DOI	https://doi.org/10.1038/s41591-019-0448-9
Status	Udgivet - 1 jun. 2019

Adgang til dokumentet

10.1038/s41591-019-0448-9

Citationsformater

Ascierto, P. A., Ferrucci, P. F., Fisher, R., Del Vecchio, M., Atkinson, V., Schmidt, H., Schachter, J., Queirolo, P., Long, G. V., Di Giacomo, A. M., Svane, I. M., Lotem, M., Bar-Sela, G., Couture, F., Mookerjee, B., Ghori, R., Ibrahim, N., Moreno, B. H., & Ribas, A. (2019). Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nature Medicine, 25(6), 941-946. https://doi.org/10.1038/s41591-019-0448-9

Ascierto, PA, Ferrucci, PF, Fisher, R, Del Vecchio, M, Atkinson, V, Schmidt, H, Schachter, J, Queirolo, P, Long, GV, Di Giacomo, AM, Svane, IM, Lotem, M, Bar-Sela, G, Couture, F, Mookerjee, B, Ghori, R, Ibrahim, N, Moreno, BH & Ribas, A 2019, 'Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma', Nature Medicine, bind 25, nr. 6, s. 941-946. https://doi.org/10.1038/s41591-019-0448-9

@article{d0ed284b0ccb42f2ac159a1232529468,

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

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.",

keywords = "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",

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

year = "2019",

month = jun,

day = "1",

doi = "10.1038/s41591-019-0448-9",

language = "English",

volume = "25",

pages = "941--946",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "nature publishing group",

number = "6",

}

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 -

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

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater