In part 2 of a phase III trial (COLUMBUS) reported in the Journal of Clinical Oncology, Paolo A. Ascierto, MD, and colleagues found evidence that MEK inhibition contributed to positive outcomes with combination BRAF/MEK inhibitor therapy in advanced BRAF V600–mutant melanoma.
Study Details
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.
Paolo A. Ascierto, MD
Key Findings
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.
The investigators concluded: “COMBO300 improved [progression-free survival, objective response rate], and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.”
Dr. Ascierto, of the Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Novartis in collaboration with Array BioPharma, which was acquired by Pfizer in July 2019. For full disclosures of the study authors, visit ascopubs.org.
