Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma

Abstract

Background: BRAF/MEK inhibitor combinations are established treatments for BRAF V600-mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report an updated analysis of the COLUMBUS (COmbined LGX818 [encorafenib] Used with MEK162 [binimetinib] in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up.

Methods: In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups.

Results: At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval [CI], 24.4-39.2) for COMBO450, 23.5 months (95% CI, 19.6-33.6) for ENCO300 and 16.9 months (95% CI, 14.0-24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio [HR], 0.61; 95% CI, 0.48-0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0-20.2), ENCO300 was 9.6 months (95% CI, 7.4-14.8) and VEM was 7.3 months (95% CI, 5.6-7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39-0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM.

Conclusions: Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600-mutated melanoma.

Keywords: BRAF V600–mutant melanoma; BRAF inhibitor; MEK inhibitor; Overall survival.

Conflict of interest statement

Conflict of interest statement P.A.A. served a consulting or advisory role for BMS, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes. P.A.A. received research funds from BMS, Roche-Genentech, Array and received travel fees from MSD. R.D. had intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi and Catalym outside the submitted work. H.J.G. reports receiving consulting fees from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen and Pierre Fabre and research funding from Bristol-Myers Squibb, Merck Sharp & Dohme and Roche outside the submitted work. K.T.F. served as a member of the Board of Directors for Clovis Oncology*, Strata Oncology*, Vivid Biosciences*, Checkmate Pharmaceuticals ; served as a member of the Corporate Advisory Board for X4 Pharmaceuticals*, PIC Therapeutics*; served as a member of the Scientific Advisory Board for Sanofi, Amgen, Asana, Adaptimmune, Fount *, Aeglea, Array BioPharma, Shattuck Labs *, Tolero, Apricity *, Oncoceutics*, Fog Pharma *, Neon, Tvardi *, served as a consultant Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Cell Medica, Debiopharm*; and as a stock shareholder. A.A. has received honoraria from, had a consulting or advisory role with or been a member of the speakers bureau for Novartis, Roche, Merck, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi and Amgen outside the submitted work and has received travel expenses from the same companies. M.M. has received personal fees from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis and Pierre Fabre outside the submitted work. G.L. has received consulting and advisory board fees from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Amicus, Boehringer-Ingelheim and Novartis outside the submitted work. C.G. has received personal fees and research funding from Novartis and Pierre Fabre during the conduct of the study. C.G. has received personal fees for presentations and consulting or advisory roles from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, NeraCare, Philogen, Roche and Sanofi and research funding from Bristol-Myers Squibb, Neracare, Roche and Sanofi outside the submitted work. D.S. has received personal fees and patients’ fees from Pierre Fabre and Array BioPharma during the conduct of the study. D.S. has received honoraria and travel expenses from, has a consulting or advisory role with, been a member of the speakers bureau for and received personal fees from, Amgen, Boehringer Ingelheim, LEO Pharma, Roche, Novartis, Hexal, InflaRx, Helsinn, GI Innovation, Immunocore, Sanofi, Neracare, Merck Sharp & Dohme, Incyte, Regeneron, 4SC, AstraZeneca, Bristol-Myers Squibb, Pierre Fabre, Merck-EMD, Pfizer, Philogen, Ultimovacs and Sun Pharma, all outside of the submitted work. I.K. is an advisory board member for and has received travel expenses from Bristol-Myers Squibb, Novartis and Merck Sharp & Dohme during the conduct of the study. R.G. received research support from Pfizer, Johnson&Johnson, Novartis, Amgen, Merck Serono; received honoraria for lectures from RochePharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck Serono, Pierre Fabre, AstraZeneca, SUN; received honoraria for advice from RochePharma, Bristol-Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Takeda, Pierre Fabre, Merck Serono, 4SC, Incyte, SUN; Support for participation in meetings from Bristol-Myers Squibb, Pierre Fabre, Merck Serono, SUN, RochePharma. J.W.B.dG. received personal fees from Roche, Bristol-Myers Squibb, Pierre Fabre, Servier, Novartis and Merck Sharp & Dohme outside the submitted work. C.L. reports receiving personal fees from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, LEO Pharma, Amgen, Biontech and Sun Pharma outside the submitted work. A.G. is an employee at Pfizer Inc. M.D.P. is an employee at Pfizer Inc. C.R. is a consultant for Pierre Fabre, Roche, Novartis, Bristol-Myers Squibb, Merck, Array BioPharma, Merck Serono and Amgen outside the submitted work.

Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.