Adjuvant Dabrafenib plus Trametinib in Stage IIIBRAF-Mutated Melanoma
| Autor: | Vanna Chiarion-Sileni, M. Mandal, A. Hauschild, Bijoyesh Mookerjee, R. Ji, Jeffrey J. Legos, John M. Kirkwood, Victoria Atkinson, Jacob Schachter, James Larkin, Richard F. Kefford, Ping Zhang, Caroline Robert, Caroline Dutriaux, M. Santinami, Andrew Haydon, Dirk Schadendorf, Georgina V. Long, Thierry Lesimple, Reinhard Dummer, Laurent Mortier, Marta Nyakas, Ruth Plummer |
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| Přispěvatelé: | University of Zurich, Long, Georgina V |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Oncology Skin Neoplasms Medizin 2700 General Medicine 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Oximes Clinical endpoint Melanoma Aged 80 and over Trametinib MEK inhibitor Imidazoles 10177 Dermatology Clinic General Medicine Middle Aged 030220 oncology & carcinogenesis Female medicine.drug Adult Proto-Oncogene Proteins B-raf medicine.medical_specialty Adolescent Combination therapy Pyridones 610 Medicine & health Pyrimidinones Young Adult 03 medical and health sciences Adjuvants Immunologic Double-Blind Method Internal medicine medicine Humans Survival analysis Aged Neoplasm Staging business.industry Dabrafenib medicine.disease Survival Analysis Surgery Clinical trial 030104 developmental biology Mutation Neoplasm Recurrence Local business |
| Zdroj: | New England Journal of Medicine. 377:1813-1823 |
| ISSN: | 1533-4406 0028-4793 0168-2083 |
| Popis: | 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.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.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; P0.001). 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.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. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .). |
| Databáze: | OpenAIRE |
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