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Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma

Lookup NU author(s): Professor Ruth Plummer

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Abstract

© Copyright 2017 Massachusetts Medical Society. All rights reserved. BACKGROUND Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-Therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-Therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P = 0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-Therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects.


Publication metadata

Author(s): Long GV, Hauschild A, Santinami M, Atkinson V, Mandal M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM

Publication type: Article

Publication status: Published

Journal: New England Journal of Medicine

Year: 2017

Volume: 377

Issue: 19

Pages: 1813-1823

Print publication date: 09/11/2017

Acceptance date: 02/04/2016

Date deposited: 29/01/2018

ISSN (print): 0028-4793

ISSN (electronic): 1533-4406

Publisher: Massachussetts Medical Society

URL: https://doi.org/10.1056/NEJMoa1708539

DOI: 10.1056/NEJMoa1708539


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