Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma

Background: This Phase III study (NCT01597908) of dabrafenib (D) + trametinib (T) compared with vemurafenib (Vem) demonstrated a 31% reduction in the risk of death for D+T compared with Vem (HR=0.69; 95%CI: 0.53–0.89; p=0.005) in pts with BRAF V600E/K mutant, metastatic melanoma at the interim analysis (N Engl J Med 2015; 372: 30–9). The adjusted stopping boundary for efficacy (p<0.0214) was crossed at the interim analysis and the study was stopped for efficacy by the Independent Data Monitoring Committee (IDMC). Rates of adverse events (AEs) were similar for both arms. There was a higher incidence of pyrexia and ejection fraction decrease with D+T, and a lower incidence of cutaneous malignancies, hyper­proliferative events, and photosensitivity with D+T compared to Vem.

Methods: Pts were randomized 1:1 to receive D (150mg twice daily) + T (2mg once daily) or Vem (960mg twice daily) as first-line therapy. Eligible pts were ≥18 years, ECOG performance status ≤1, and had histologically confirmed unresectable stage IIIC or IV, BRAF V600E/K mutant cutaneous melanoma. The primary endpoint was OS; secondary endpoints were PFS, overall response rate (ORR), duration of response (DoR), and safety.

Results: From June 2012 to October 2013, 1,645 pts were registered and 704 were randomized 1:1 to one of two treatment arms (352 to D+T, 352 to Vem). The updated (March 13^th 2015) OS analysis demonstrated a statistically significant improvement in OS for D+T over Vem (HR=0.66 [95%CI: 0.53–0.81; p<0.001]) and median OS of 25.6 vs 18 months. The updated analysis reported a statistically significant improvement in PFS for D+T over Vem (HR=0.61 [95%CI: 0.51–0.73], p<0.001) and median PFS of 12.6 and 7.3 months, respectively. The 2-year estimate of OS and updated efficacy and safety results will be presented.

Conclusions: Updated OS analysis confirmed improvement in OS favoring D+T over Vem with medians of 25.6 versus 18 months. Two-year OS rates and additional efficacy and safety analysis will be presented.

Conflict of interest: Ownership: J Legos reported equity ownership with GSK. B Mookerjee reported equity ownership with GSK, Incyte Corporation, and AstraZeneca. Advisory Board: P Rutkowski participated in an Advisory Committee for Novartis, Roche, BMS, and MSD. R Dummer participated in an Ad Board with Roche, BMS, GSK, MSD, Novartis. V Chiarion-Sileni participated in an Advisory Committee for BMS, GSK, Roche, and Merck. I Krajsová participated in an Advisory Committee for BMS. Board of Directors: P Rutkowski was a member of the board of directors for Novartis, Roche, BMS, and MSD. V Chiarion-Sileni was a member of the board of directors for BMS, GSK, Roche, and Merck. I was a member of the board of directors for BMS. Corporate-sponsored Research: M Lichinitser received research funding from GSK. R Dummer received research funding from Roche, BMS, GSK, MSD, Novartis. K Drucis received research funding from GSK. A Hauschild received research funding from Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma. Other Substantive Relationships: C Robert acted as a consultant for GSK, Novartis, Merck, BMS, Amgen, and Roche. P Rutkowski received honoraria from Novartis, GSK, Roche, Amgen, Pfizer, BMS, MSD, and Bayer and participated in a speakers bureau for Novartis and Pfizer. L Mortier reports personal fees from GSK, during the conduct of the study. A Hauschild acted as a consultant for Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche and received honoraria from Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche. B Mookerjee and J Legos are employees of GSK. D Schadendorf acted as a consultant and received honoraria from, and participated in a speakers bureau for GSK, Novartis, Roche, Amgen, BMS, Boehringer Ingelheim, and Merck/MSD.