In part 2 of a phase III trial (COLUMBUS) reported in the Journal of Clinical Oncology, Ascierto et al found evidence that MEK inhibition contributed to positive outcomes with combination BRAF/MEK inhibitor therapy in advanced BRAF V600–mutant melanoma. As stated by the investigators: “In COLUMBUS part 1, patients with advanced BRAF V600–mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival … versus vemurafenib (part 1 primary endpoint) and ENCO300 (part 1 key secondary endpoint; not statistically significant). Part 2, requested by the U.S. [Food and Drug Administration] evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms.” In part 2, 344 patients from sites in 24 countries were randomly assigned 3:1 between March 2015 and November 2015 to receive COMBO300 (n = 258) or ENCO300 (n = 86). Analyses included the ENCO300 group of 194 patients from part 1, yielding a combined ENCO300 group of 280 patients. The major outcome measure in the current analysis was progression-free survival assessed by blinded independent review committee.
Median follow-up was 54.4 months in the COMBO300 group, 43.5 months in the part 1/2 ENCO300 group, and 57.1 months in the part 2 ENCO300 group. Median progression-free survival was 12.9 months (95% CI = 10.9–14.9 months) in the COMBO300 group vs 9.2 months (95% CI = 7.4–11.1 months) in the part 1/2 ENCO300 group (hazard ratio [HR] = 0.74, 95% CI = 0.60–0.92, P = .003) and 7.4 months (95% CI = 5.6–9.2 months) in the part 2 ENCO300 group (HR = 0.60, 95% CI = 0.45–0.80, P = .0003). Objective response rates on blinded independent review committee assessment were 68% (95% CI = 62%–74%) in the COMBO300 group vs 51% (95% CI = 45%–57%) in the part 1/2 ENCO300 group. Grade 3 or 4 adverse events occurred in 58.8% of the COMBO300 group vs 67.4% of the part 1/2 ENCO300 group. Any-grade adverse events that were ≥ 10% more common in the COMBO300 group were diarrhea and increased creatine phosphokinase; those adverse events that were ≥ 10% more common in the part 1/2 ENCO300 group were skin toxicities, arthralgia, myalgia, headache, and insomnia.