Abstract 4143
Background
The addition of a MEK inhibitor (MEKi) to a BRAF inhibitor (BRAFi) in BRAF V600-mutant metastatic melanoma improves efficacy, including progression-free survival (PFS) and objective response rate (ORR), and attenuates some BRAFi−associated toxicities. Part 1 of the COLUMBUS study met its primary endpoint. The BRAFi ENCO 450 mg once daily (QD) + the MEKi BINI 45 mg twice daily (BID; COMBO450) improved PFS vs vemurafenib (VEM) alone and ENCO 300 mg QD (ENCO300) alone in patients (pts) with advanced BRAF V600-mutant melanoma. The tolerability of COMBO450 was favorable compared with VEM or ENCO300. In Part 2, the contribution of BINI to the combination was further evaluated by maintaining the same dose of ENCO in the combination (ENCO 300 mg QD + BINI 45 mg BID; COMBO300) and comparator arms (ENCO300 alone; ClinicalTrials.gov, NCT01909453; EudraCT, 2013-001176-38).
Methods
Pts were randomized 3:1 to COMBO300 or ENCO300. Data from ENCO300 arms in Parts 1 + 2 were combined for the primary efficacy comparison of PFS by independent blinded central review (BCR). Other analyses included PFS for COMBO300 vs ENCO300 (Part 2 only), ORR, complete response (CR) and partial response (PR) by BCR and local review, and safety.
Results
Pt characteristics are presented in the Table. Median PFS (95% CI) for COMBO300 was 12.9 mo (10.1–14.0) vs 9.2 mo (7.4–11.0) for ENCO300 (Parts 1 + 2) and 7.4 mo (5.6–9.2) for ENCO300 (Part 2). The hazard ratio (HR) for COMBO300 was 0.77 (0.61–0.97; P = 0.029, 2-sided) vs ENCO300 (Parts 1 + 2) and 0.57 (0.41–0.78; P
Conclusions
COMBO300 meaningfully improved PFS, ORR, and tolerability vs ENCO300, confirming the contribution of BINI to both efficacy and safety.
Clinical trial identification
Trial protocol number, CMEK162B2301 (release date, July 13, 2015)
Legal entity responsible for the study
Array BioPharma Inc
Funding
Array BioPharma Inc and Novartis Pharmaceuticals Corporation
Disclosure
R. Dummer: Honoraria from and consulting/advisory role for Roche, Bristol-Myers Squibb, GSK, MSD, Novartis, and Amgen; research funding from Roche, Bristol-Myers Squibb, GSK, MSD, and Novartis. P.A. Ascierto: Consulting fees from Bristol-Myers Squibb, Roche/Genentech, MSD, Ventana, Novartis, Amgen, and Array BioPharma; research funding from Bristol-Myers Squib, Roche/Genentech, Ventana, and Array BioPharma H. Gogas: Consultant for Roche, Bristol-Myers Squibb, MSD, Novartis, and Amgen. A. Arance: Honoraria from and consulting/advisory role and speakers bureau for Novartis, Roche, MSD, and Bristol-Myers Squibb; travel expenses from Roche and Bristol-Myers Squibb. M. Mandala: Honoraria from Novartis, GSK, Bristol-Myers Squibb, MSD, and Roche; speakers bureau for Novartis, GSK, Roche, and Bristol-Myers Squibb; advisory board member for Novartis, Amgen, MSD, and Bristol-Myers Squibb; research funding from Roche. C. Garbe: Honoraria and travel expenses from and served in a consulting/advisory role and speakers bureau member for Amgen, Bristol-Myers Squibb, MSD, Novartis, Roche, and Philogen; research funding for University Hospital Tübingen from Bristol-Myers Squibb, Novartis, and Roche. D. Schadendorf: Honoraria and travel expenses from and consulting/advisory role and speakers bureau for Amgen, Bristol-Myers Squibb, Novartis, Roche, and MSD; research funding for University Hospital Essen from Amgen, Bristol-Myers Squibb, Novartis, Roche, and MSD. I. Krajsová: Advisory board member for Bristol-Myers Squibb, Novartis, Roche, MSD; travel expenses from Bristol-Myers Squibb and MSD. R. Gutzmer: Consulting fees and/or honoraria from Roche, Bristol-Myers Squibb, MSD, GSK, Novartis, Almirall, LEO, Amgen, Pfizer, Merck Serono, Boehringer Ingelheim; research funding from Roche, Novartis, Pfizer, Pierre Fabre, Johnson & Johnson; travel expenses from Bristol-Myers Squibb, Roche. V. Chiarion Sileni: Honoraria received from Novartis, GSK, Bristol-Myers Squib, MSD, and Roche; speakers bureau for Novartis, GSK, Roche, and Bristol-Myers Squibb; advisory board member for Novartis, Amgen, MSD, Bristol-Myers Squibb, and Roche. J.W.B. de Groot: Consulting/advisory role for Amgen, Bayer, Celgene, Roche, Bristol-Myers Squibb, GSK, MSD, and Merck Serono. N. Yamazaki: Advisory role for Chugai Pharma, Bristol-Myers Squibb Japan, and Ono Pharmaceutical; honoraria from Chugai Pharma, Bristol-Myers Squibb Japan, Ono Pharmaceutical, GlaxoSmithKline, Takeda, AstraZeneca Japan, Boehringer Ingelheim, and Maruho. C. Loquai: Advisory board member for Roche, Novartis, Bristol-Myers Squibb, MSD, BioNTech, Pierre Fabre, and Amgen; speakers fees from Roche, Novartis, B Bristol-Myers Squibb MS, and MSD; travel expenses from Roche, Novartis, Bristol-Myers Squibb, MSD, and Amgen. L.A. de Parseval: Employee of Novartis Pharma AG; may own stock or stock options. M. Pickard: Employee of Array BioPharma; may own stock or stock options. V. Sandor: Employee/leadership role at Array BioPharma; stock or other ownership of Array BioPharma and Incyte Corp. C. Robert: Consultant for Roche, Novartis, Bristol-Myers Squibb, MSD, and Amgen. K.T. Flaherty: Honoraria from and consulting/advisory role for Novartis and Array BioPharma; research funding from Novartis. All other authors have declared no conflicts of interest.