Combi-V: a Randomised, Open-Label, Phase III Study Comparing the Combination of Dabrafenib (D) and Trametinib (T) with Vemurafenib (V) As First-Line Therapy in Patients (Pts) with Unresectable or Metastatic Braf V600E/K Mutation-Positive Cutaneous Melanoma
Authors: C. Robert, B. Karaszewska, J. Schachter, P. Rutkowski, A. Mackiewicz, D. Stroiakovski, M. Lichinitser, R. Dummer, F. Grange, L. Mortier, V. Chiarion-Sileni, K. Drucis, I. Krajsova, A. Hauschild, P. Sun, S.D. Rubin, J. Legos, W.A. Crist, S.M. Little, D. Schadendorf
Journal: Annals of Oncology (2014)

ABSTRACT   Aim: BRAFi (D) and MEKi (T) each demonstrated superior progression-free survival (PFS) vs. chemotherapy in pts with BRAF V600E/K mutation-positive metastatic melanoma (MM). However, the emergence of disease resistance and development of cutaneous squamous cell carcinoma (cuSCC) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects as shown in the Phase I/II study of D + T combination therapy vs. D monotherapy (NCT01072175) and the Phase III study of D + T combination therapy vs. D monotherapy (NCT01584648), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01597908) was conducted to establish superiority of D + T combination over V with respect to overall survival (OS) in pts with BRAF V600E/K mutation-positive MM.  Methods: Pts were randomised 1:1 to receive D (150 mg twice daily [BID]) and T (2 mg once daily) vs. V monotherapy (960 mg BID) as first-line therapy. Eligible pts were ≥ 18 years old and had an ECOG performance status ≤ 1, with histologically confirmed, unresectable stage IIIC or IV, BRAF V600E/K mutation-positive MM. The primary endpoint was OS; secondary endpoints were PFS, ORR, duration of response, and safety. Crossover was prohibited. A pre-specified interim OS analysis was performed when 77% (222/288) of the total number of expected deaths, required for the protocol-specified final analysis, were observed; the study could be stopped for efficacy if the one-sided P value was   Results: From June 2012 to Oct 2013, 704 pts were randomised (352 to each arm). IDMC recommended stopping study based on an interim analysis which demonstrated an OS benefit that crossed the pre-specified efficacy stopping boundary for D + T combination. Rates of adverse events were generally similar for both arms and consistent with data from previous trials. Full efficacy and safety results will be presented at the meeting.  Conclusions: D + T demonstrated a significant improvement in OS compared with V in pts with BRAF V600E/K mutation-positive MM.  Disclosure: C. Robert: has received fees for Advisory Board participation from Bristol-Meyers Squibb, Roche, Merck, GlaxoSmithKline, Novartis and Amgen; P. Rutkowski: receives personal fees Novartis, Pfizer, GSK, and Roche, in addition to travel grants and fees for participation in speakers bureau and Advisory Boards from GSK and Novartis; R. Dummer: received grants and personal fees from GSK, Roche, Novartis, MSD and BMS; L. Mortier: received personal fees from GSK; V. Chiarion-Sileni: receiving compensation for Advisory Board participation GlaxoSmithKline, Bristol-Meyers Squibb and Roche; A. Hauschild: Consult, Hon and Trial funding: mgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche; P. Sun, S. Rubin and J. Legos: is an employee of GlaxoSmithKline and owns stock in the company; W. Crist: is an employee of GlaxoSmithKline; S.M. Little: is an employee and owns stock in GSK; D. Schadendorf: received personal fees, other support, and non-financial support from GlaxoSmithKline, Roche, Novartis, Amgen, Bristol-Meyers Squibb and MSD/Merck, and grants from MSD/Merck. All other authors have declared no conflicts of interest.