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

• Published in: The Lancet (British edition) Vol. 386; no. 9992; pp. 444 - 451
• Main Authors: Long, Georgina V, MD, Stroyakovskiy, Daniil, MD, Gogas, Helen, MD, Levchenko, Evgeny, MD, de Braud, Filippo, MD, Larkin, James, FRCP, Garbe, Claus, Prof, Jouary, Thomas, MD, Hauschild, Axel, Prof, Grob, Jean-Jacques, Prof, Chiarion-Sileni, Vanna, MD, Lebbe, Celeste, Prof, Mandalà, Mario, MD, Millward, Michael, Prof, Arance, Ana, MD, Bondarenko, Igor, Prof, Haanen, John B A G, Prof, Hansson, Johan, Prof, Utikal, Jochen, Prof, Ferraresi, Virginia, MD, Kovalenko, Nadezhda, Prof, Mohr, Peter, MD, Probachai, Volodymr, MD, Schadendorf, Dirk, Prof, Nathan, Paul, MD, Robert, Caroline, MD, Ribas, Antoni, Prof, DeMarini, Douglas J, PhD, Irani, Jhangir G, MA, Swann, Suzanne, PhD, Legos, Jeffrey J, PhD, Jin, Fan, MD, Mookerjee, Bijoyesh, MD, Flaherty, Keith, MD
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2015; Elsevier Limited
• Subjects: Adult; Aged; Aged, 80 and over; Chemotherapy; Clinical trials; Disease-Free Survival; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Imidazoles - administration & dosage; Internal Medicine; Male; Medicin och hälsovetenskap; Melanoma; Melanoma - drug therapy; Metastasis; Middle Aged; Mutation; Oximes - administration & dosage; Proto-Oncogene Proteins B-raf - genetics; Pyridones - administration & dosage; Pyrimidinones - administration & dosage; Studies; Survival; Survival analysis; Treatment Outcome; Young Adult
• ISSN: 0140-6736; 1474-547X; 1474-547X
• DOI: 10.1016/S0140-6736(15)60898-4

Summary 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.