Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
Paolo A. Ascierto
,
Grant R. Goodman
,
Brian Simmons
,
Chenglin Ye
,
Yibing Yan
,
Gabriela Cinat
,
Luis Enrique Fein
,
Michael Brown
,
Alexander Guminski
,
Andrew Haydon
,
Adnan Khattak
,
Catriona McNeil
,
Phillip Parente
,
Jeremy Power
,
Rachel Roberts-Thomson
,
Shahneen Sandhu
,
Craig Underhill
,
Suresh Varma
,
Thomas Berger
,
Ahmad Awada
,
Nathalie Blockx
,
Véronique Buyse
,
Jeroen Mebis
,
Fabio Andre Franke
,
Sergio Jobim De Azevedo
,
Nicolas Silva Lazaretti
,
Rahima Jamal
,
Catalin Mihalcioiu
,
Teresa Petrella
,
Kerry Savage
,
Xinni Song
,
Ralph Wong
,
Nina Dabelić
,
Stjepko Plestina
,
Željko Vojnović
,
Petr Arenberger
,
Ivo Kocak
,
Ivana Krajsová
,
Eugen Kubala
,
Bohuslav Melichar
,
Yvetta Vantuchova
,
Kadri Putnik
,
Brigitte Dreno
,
Caroline Dutriaux
,
Jean-Jacques Grob
,
Pascal Joly
,
Jean Philippe Lacour
,
Nicolas Meyer
,
Laurent Mortier
,
Luc Thomas
,
Michael Fluck
,
THILO GAMBICHLER
,
Jessica Hassel
,
Axel Hauschild
,
Dirk Schadendorf
,
Paul Donnellan
,
John McCaffrey
,
Derek Power
,
Samuel Ariad
,
Gil Bar-Sela
,
Daniel Hendler
,
Ilan Ron
,
Jacob Schachter
,
Paolo Ascierto
,
ALFREDO BERRUTI
,
Luca Bianchi
,
Vanna Chiarion Sileni
,
Francesco Cognetti
,
Riccardo Danielli
,
Anna Maria Di Giacomo
,
Luca Gianni
,
Aron Goldhirsch
,
Michele Guida
,
Michele Maio
,
Mario Mandalá
,
Paolo Marchetti
,
Paola Queirolo
,
Armando Santoro
,
Ellen Kapiteijn
,
Andrzej Mackiewicz
,
Piotr Rutkowski
,
Paula Ferreira
,
Lev Demidov
,
Georgy Gafton
,
Yulia Makarova
,
Zoran Andric
,
Nada Babović
,
Darjana Jovanovic
,
Lidija Kandolf Sekulovic
,
Graham Cohen
,
Lydia Dreosti
,
Daniel Vorobiof
,
Maria Teresa Curiel Garcia
,
Roberto Díaz-Beveridge
,
Margarita Majem Tarruella
,
Ivan Marquez-Rodas
,
Jose M Puliats Rodriguez
,
Antonio Rueda Dominguez
,
Marianne Maroti
,
Karin Papworth
,
Olivier Michielin
,
Igor Bondarenko
,
Ewan Brown
,
Pippa Corrie
,
Mark Harries
,
Christopher Herbert
,
Satish Kumar
,
Agustín Martín Clavijo
,
Mark Middleton
,
Poulam Patel
,
Toby Talbot
,
Sanjiv Agarwala
,
Paul Chapman
,
Robert Conry
,
Gary Doolittle
,
Tara Gangadhar
,
Sigrun Hallmeyer
,
Omid Hamid
,
Leonel Hernandez-Aya
,
Douglas Johnson
,
Frederic Kass
,
Tatjana Kolevska
,
Karl Lewis
,
Scott Lunin
,
April Salama
,
Branimir Sikic
,
Bradley Somer
,
David Spigel
,
Eric Whitman
Publication type: Journal Article
Publication date: 2018-04-01
scimago Q1
wos Q1
SJR: 11.319
CiteScore: 50.8
Impact factor: 35.9
ISSN: 14702045, 14745488
PubMed ID:
29477665
Oncology
Abstract
Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma.BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419.The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug.The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.F Hoffman-La Roche Ltd.
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Total citations:
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Citations from 2024:
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(12.57%)
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Ascierto P. A. et al. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial // The Lancet Oncology. 2018. Vol. 19. No. 4. pp. 510-520.
GOST all authors (up to 50)
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Ascierto P. A. et al. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial // The Lancet Oncology. 2018. Vol. 19. No. 4. pp. 510-520.
Cite this
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@article{2018_Ascierto,
author = {Paolo A. Ascierto and Grant R. Goodman and Brian Simmons and Chenglin Ye and Yibing Yan and Gabriela Cinat and Luis Enrique Fein and Michael Brown and Alexander Guminski and Andrew Haydon and Adnan Khattak and Catriona McNeil and Phillip Parente and Jeremy Power and Rachel Roberts-Thomson and Shahneen Sandhu and Craig Underhill and Suresh Varma and Thomas Berger and Ahmad Awada and Nathalie Blockx and Véronique Buyse and Jeroen Mebis and Fabio Andre Franke and Sergio Jobim De Azevedo and Nicolas Silva Lazaretti and Rahima Jamal and Catalin Mihalcioiu and Teresa Petrella and Kerry Savage and Xinni Song and Ralph Wong and Nina Dabelić and Stjepko Plestina and Željko Vojnović and Petr Arenberger and Ivo Kocak and Ivana Krajsová and Eugen Kubala and Bohuslav Melichar and Yvetta Vantuchova and Kadri Putnik and Brigitte Dreno and Caroline Dutriaux and Jean-Jacques Grob and Pascal Joly and Jean Philippe Lacour and Nicolas Meyer and Laurent Mortier and Luc Thomas and others},
title = {Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial},
journal = {The Lancet Oncology},
year = {2018},
volume = {19},
publisher = {Elsevier},
month = {apr},
url = {https://doi.org/10.1016/s1470-2045(18)30106-2},
number = {4},
pages = {510--520},
doi = {10.1016/s1470-2045(18)30106-2}
}
Cite this
MLA
Copy
Ascierto, Paolo A., et al. “Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.” The Lancet Oncology, vol. 19, no. 4, Apr. 2018, pp. 510-520. https://doi.org/10.1016/s1470-2045(18)30106-2.