BACKGROUND: Combined BRAF-MEK inhibitor therapy is the standard of care for 
BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor 
with unique target-binding properties, alone or in combination with the MEK 
inhibitor binimetinib, versus vemurafenib in patients with advanced 
BRAFV600-mutant melanoma.
METHODS: COLUMBUS was conducted as a two-part, randomised, open-label phase 3 
study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or 
older and had histologically confirmed locally advanced (American Joint 
Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic 
cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K 
mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1; and were treatment naive or had progressed on or after previous first-line 
immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) 
via interactive response technology to receive either oral encorafenib 450 mg 
once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib 
group), oral encorafenib 300 mg once daily (encorafenib group), or oral 
vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was 
progression-free survival by blinded independent central review for encorafenib 
plus binimetinib versus vemurafenib. Efficacy analyses were by 
intention-to-treat. Safety was analysed in patients who received at least one 
dose of study drug and one postbaseline safety assessment. The results of part 2 
will be published separately. This study is registered with ClinicalTrials.gov, 
number NCT01909453, and EudraCT, number 2013-001176-38.
FINDINGS: Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened 
patients were randomly assigned to either the encorafenib plus binimetinib group 
(n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a 
median follow-up of 16·6 months (95% CI 14·8-16·9), median progression-free 
survival was 14·9 months (95% CI 11·0-18·5) in the encorafenib plus binimetinib 
group and 7·3 months (5·6-8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 
95% CI 0·41-0·71; two-sided p<0·0001). The most common grade 3-4 adverse events 
seen in more than 5% of patients in the encorafenib plus binimetinib group were 
increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine 
phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group 
they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), 
myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it 
was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths 
except for one death in the combination group, which was considered possibly 
related to treatment by the investigator.
INTERPRETATION: Encorafenib plus binimetinib and encorafenib monotherapy showed 
favourable efficacy compared with vemurafenib. Overall, encorafenib plus 
binimetinib appears to have an improved tolerability profile compared with 
encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new 
treatment option for patients with BRAF-mutant melanoma.
FUNDING: Array BioPharma, Novartis.