Dummer R, et al. - Given that, encorafenib plus binimetinib and encorafenib alone improved progression-free survival vs vemurafenib in patients with BRAF ^V600-mutant melanoma in the COLUMBUS trial, this study presents the outcomes regarding the secondary endpoint of overall survival. Compared with vemurafenib, the combination of encorafenib + binimetinib had good tolerability and offered clinically meaningful effectiveness reflected by improvements in both progression-free survival and overall survival. In patients with BRAF ^V600-mutant melanoma, the combination of encorafenib + binimetinib will probably become a vital therapeutic option.

Methods

• A two-part, randomized, open-label, phase 3 study (COLUMBUS) was conducted at 162 hospitals in 28 countries including patients aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF ^V600E or BRAF ^V600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy.
• In part 1 of the study, random assignment (1:1:1) of patients to 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) was done by using interactive response technology.
• By the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status, the randomization was stratified.
• Progression-free survival with encorafenib plus binimetinib vs vemurafenib (primary outcome of the trial) was reported previously.
• Researchers present the prespecified interim overall survival analysis and outcomes of intent to treat efficacy analyses.
• For safety analysis, patients who received at least one dose of study drug were selected.
• In part 2 of the study, which was initiated at the request of the US Food and Drug Administration, encorafenib 300 mg once daily plus binimetinib 45 mg twice daily was compared with encorafenib 300 mg once daily alone to better understand the contribution of binimetinib to the combination therapy.
• This trial is ongoing and the results of part 2 will be published separately.

Results

• Random assignment of 577 of 1,345 screened patients to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191) was carried out between December 30, 2013, and April 10, 2015.
• A median follow-up of 36.8 months for overall survival was also carried out (95% CI 35.9–37.5).
• With encorafenib plus binimetinib and with vemurafenib, the estimated median overall survival was 33.6 months (95% CI 24.4–39.2) and 16.9 months (14.0–24.5), respectively (hazard ratio 0.61 [95% CI 0.47–0.79]; two-sided p<0.0001).
• No substantial change was seen in the most common grade 3 or 4 adverse events from the first report; increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]) were documented in more than 5% of patients treated with encorafenib plus binimetinib; those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]).
• Arthralgia (11 [6%] of 186 patients) was the most common grade 3 or 4 adverse event seen with vemurafenib.
• One death was reported in the combination treatment group, which was considered by the investigator to be possibly associated with treatment.