Dummer R, et al. - For treating advanced BRAF^V600-mutant melanoma, the efficacy of alone or combined administration of encorafenib (a BRAF inhibitor with unique target-binding properties) with the MEK inhibitor binimetinib was compared with that of vemurafenib. Favourable efficacy of encorafenib plus binimetinib and encorafenib monotherapy was observed in comparison to vemurafenib. Relative to encorafenib or vemurafenib, encorafenib plus binimetinib appeared to have an improved tolerability profile. Encorafenib + binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.

• COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries, including patients aged 18 years or older, having 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 BRAF^V600E or BRAF^V600Kmutation; 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.
• Part 1 of the study involved random assignment (1:1:1) of patients, 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 vs vemurafenib, and efficacy analyses were by intention-to-treat.
• Researchers assessed safety in patients who received at least one dose of study drug and one postbaseline safety assessment.

• Out of a total of 1345 screened patients, 577 were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191) between Dec 30, 2013, and April 10, 2015.
• A median follow-up of 16·6 months (95% CI 14·8–16·9) showed median progression-free survival of 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).
• Increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]) were documented as the most common grade 3–4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group.
• They were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]) in the encorafenib group and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients).
• No treatment-related deaths were reported except for one death in the combination group, which was considered possibly associated with treatment by the investigator.