Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial

Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko, Filippo De Braud, James Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean Jacques Grob, Vanna Chiarion-Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Ana Arance, Igor Bondarenko, John B.A.G. Haanen, Johan Hansson, Jochen Utikal, Virginia FerraresiNadezhda Kovalenko, Peter Mohr, Volodymr Probachai, Dirk Schadendorf, Paul Nathan, Caroline Robert, Antoni Ribas, Douglas J. Demarini, Jhangir G. Irani, Suzanne Swann, Jeffrey J. Legos, Fan Jin, Bijoyesh Mookerjee, Keith Flaherty

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    1140 Citations (Scopus)

    Résumé

    Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline.

    langue originaleAnglais
    Pages (de - à)444-451
    Nombre de pages8
    journalThe Lancet
    Volume386
    Numéro de publication9992
    Les DOIs
    étatPublié - 1 août 2015

    Contient cette citation