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

Research output: Contribution to journalLetter

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.

Original languageEnglish
Pages (from-to)941-946
Number of pages6
JournalNature Medicine
Volume25
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

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Melanoma
Placebos
Blocking Antibodies
Mitogen-Activated Protein Kinase Kinases
Transaminases
Tumors
Hazards
Durability
Therapeutics
Disease-Free Survival
Confidence Intervals
dabrafenib
pembrolizumab
trametinib
Exanthema
Pneumonia
Fever
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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.

In: Nature Medicine, Vol. 25, No. 6, 01.06.2019, p. 941-946.

Research output: Contribution to journalLetter

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, vol. 25, no. 6, pp. 941-946. https://doi.org/10.1038/s41591-019-0448-9
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. / Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. In: Nature Medicine. 2019 ; Vol. 25, No. 6. pp. 941-946.
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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.",
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AU - Ascierto, Paolo Antonio

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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

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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.

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