KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma

Background In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survi...

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Autores principales:	Antoni Ribas, Inge Marie Svane, Paolo Antonio Ascierto, Victoria Atkinson, Razi Ghori, Anna Maria Di Giacomo, Georgina V Long, Henrik Schmidt, Jacob Schachter, Eduard Gasal, Paola Queirolo, Michal Lotem, Michele Del Vecchio, Pier Francesco Ferrucci, Rosalie Stephens, Mahmoud Abu-Amna, Scott J Diede, Elizabeth S Croydon
Formato:	article
Lenguaje:	EN
Publicado:	BMJ Publishing Group 2020
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/06d6c0dbe8904dc09538e628a3bd82da
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spelling	oai:doaj.org-article:06d6c0dbe8904dc09538e628a3bd82da2021-12-04T18:30:05ZKEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma10.1136/jitc-2020-0018062051-1426https://doaj.org/article/06d6c0dbe8904dc09538e628a3bd82da2020-10-01T00:00:00Zhttps://jitc.bmj.com/content/8/2/e001806.fullhttps://doaj.org/toc/2051-1426Background In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.Methods The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.Results Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3–5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.Conclusion In BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.Antoni RibasInge Marie SvanePaolo Antonio AsciertoVictoria AtkinsonRazi GhoriAnna Maria Di GiacomoGeorgina V LongHenrik SchmidtJacob SchachterEduard GasalPaola QueiroloMichal LotemMichele Del VecchioPier Francesco FerrucciRosalie StephensMahmoud Abu-AmnaScott J DiedeElizabeth S CroydonBMJ Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Antoni Ribas Inge Marie Svane Paolo Antonio Ascierto Victoria Atkinson Razi Ghori Anna Maria Di Giacomo Georgina V Long Henrik Schmidt Jacob Schachter Eduard Gasal Paola Queirolo Michal Lotem Michele Del Vecchio Pier Francesco Ferrucci Rosalie Stephens Mahmoud Abu-Amna Scott J Diede Elizabeth S Croydon KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
description	Background In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.Methods The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.Results Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3–5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.Conclusion In BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
format	article
author	Antoni Ribas Inge Marie Svane Paolo Antonio Ascierto Victoria Atkinson Razi Ghori Anna Maria Di Giacomo Georgina V Long Henrik Schmidt Jacob Schachter Eduard Gasal Paola Queirolo Michal Lotem Michele Del Vecchio Pier Francesco Ferrucci Rosalie Stephens Mahmoud Abu-Amna Scott J Diede Elizabeth S Croydon
author_facet	Antoni Ribas Inge Marie Svane Paolo Antonio Ascierto Victoria Atkinson Razi Ghori Anna Maria Di Giacomo Georgina V Long Henrik Schmidt Jacob Schachter Eduard Gasal Paola Queirolo Michal Lotem Michele Del Vecchio Pier Francesco Ferrucci Rosalie Stephens Mahmoud Abu-Amna Scott J Diede Elizabeth S Croydon
author_sort	Antoni Ribas
title	KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
title_short	KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
title_full	KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
title_fullStr	KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
title_full_unstemmed	KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
title_sort	keynote-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in braf-mutant melanoma
publisher	BMJ Publishing Group
publishDate	2020
url	https://doaj.org/article/06d6c0dbe8904dc09538e628a3bd82da
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KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma

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