The evidence supporting this protocol is provided by a two part phase III multicentre, open label international randomised trial (COLUMBUS) involving 577 patients, with unresectable stage III or metastatic melanoma; with a BRAF V600E and/or BRAF V600K mutation who were treatment naive or had progressed on or after previous first-line immunotherapy.r,r
In Part 1, between December 2013 and April 2015, patients were randomised into one of three groups: the encorafenib plus binimetinib group (n=192) which received oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily, the encorafenib group (n=194) which received oral encorafenib 300 mg once daily, or the vemurafenib group (n=191) which received oral vemurafenib 960 mg twice daily. At the request of the FDA, Part 2 investigated encorafenib 300 mg once daily plus binimetinib 45 mg twice daily versus encorafenib monotherapy 300 mg once daily.
The primary endpoint was progression-free survival (PFS) by blinded independent central review for encorafenib plus binimetinib versus vemurafenib.
Secondary end points included PFS for encorafenib plus binimetinib versus encorafenib, PFS for encorafenib versus vemurafenib; best overall response, overall response, disease control, duration of response, time to response, and safety of encorafenib with binimetinib and encorafenib alone; overall survival for encorafenib plus binimetinib versus encorafenib, and encorafenib versus vemurafenib; and quality of life.r
Efficacy
An updated analysis was conducted after a median follow-up of 48.8 months for OS. The median OS was 33.6 months (95% CI, 24.4 to 39.2) in the encorafenib plus binimetinib group, 23.5 months (95% CI, 19.6 to 33.6) in the encorafenib group and 16.9 months (95% CI, 14.0 to 24.5) in the vemurafenib group. The updated median PFS was 14.9 months (95% CI, II.0 to 20.2) in the encorafenib plus binimetinib group, 9.6 months (95% CI, 7.4 to 14.8) in the encorafenib group and 7.3 months (95% CI, 5.6 to 7.9) in the vemurafenib group.r
In subgroup analysis, all treatments performed more poorly in patients with high lactate dehydrogenase (LDH) than in those with normal LDH across all treatment arms. The median OS in the high LDH subgroup demonstrated a trend favouring the encorafenib plus binimetinib arm (11.4 months) compared with the vemurafenib arm (9.6 months), however these results were not statistically significant (HR 0.92; 95% CI, 0.62 to 1.39).
Kaplan-Meier curves of progression-free survival (PFS)r
© Eur J Cancer 2020
Overall response according to treatment groupr
© Eur J Cancer 2020
Kaplan-Meier curves of overall survival (OS)r
© Eur J Cancer 2020
Quality of life outcomes are to be reported separately.
Toxicity
68% of patients experienced grade 3/4 adverse events in the encorafenib plus binimetinib group. This was similar to the encorafenib and vemurafenib groups, with 68% and 66% respectively. Burden of toxicity was noted to lessen over time. Adverse events lead to discontinuation in 16% of the encorafenib plus binimetinib, 15% of the encorafenib group and 17% of the vemurafenib group. Dose reduction/interruption occurred in 55%, 71% and 62% respectively.r
A systematic review and meta-analysis of several randomised trials in patients with melanoma being treated with BRAF/MEK inhibitors, demonstrated increased risk of cardiotoxicity including left ventricular dysfunction, arterial hypertension and pulmonary embolism with the BRAF/MEK inhibitor combination compared with BRAF monotherapy.
Adverse eventsr
© Eur J Cancer 2020