Addition of Binimetinib to Encorafenib Demonstrated Efficacy, Safety Among Patients With Advanced, Unresectable BRAFV600-Mutant Melanoma

Results From Part 2 of the Phase 3 COLUMBUS Trial 

According to results from part 2 of the phase 3 COLUMBUS trial, the addition of binimetinib to encorafenib improved progression-free survival (PFS), overall response rate (ORR), and had a favorable safety profile compared to encorafenib alone among patients with advanced, unresectable BRAFV600-mutant melanoma.

In part 1 of this trial, patients with advanced, unresectable BRAFV600-mutant melanoma were randomized on a 1-to-1-to-1 basis to receive 450 mg encorafenib once daily plus 45 mg binimetinib twice daily, 960 mg vemurafenib twice daily, or 300 mg encorafenib once daily. The primary end point was PFS comparison between the encorafenib plus binimetinib arm and the vemurafenib arm. The key secondary end point was PFS comparison between the encorafenib plus binimetinib arm and the encorafenib arm. A previously reported, encorafenib plus binimetinib improved PFS compared to both vemurafenib and encorafenib; however, the improvement between patients in the encorafenib plus binimetinib and encorafenib arms was not statistically significant.

According to Paolo A. Ascierto, MD, National Tumor Institute Fondazione G. Pascale, Naples, Italy, and coauthors, “Part 2 [was] requested by the US Food and Drug Administration [and] 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) and [encorafenib] arms.”

In this analysis of part 2, 344 patients were randomized on a 3-to-1 basis between March 19, 2015, and November 12, 2015, to receive either once daily encorafenib plus twice daily binimetinib (n =256) or once daily encorafenib (n =86). Per study protocol, data from patients treated in the encorafenib arm (n = 280) in part 1 was combined with data from patients treated in the encorafenib arm in part 2 for data analysis. The primary end point was PFS analysis by blinded independent review committee (BIRC) and other analyses included ORR, overall survival (OS), and safety.

The median follow-up among patients treated with encorafenib in part 1 was 40.8 months and among patients treated in part 2, 57.1 months. Median PFS was 12.9 months in the encorafenib plus binimetinib arm compared with a median PFS of 9.2 in the encorafenib arm of part 1 and 7.4 months in the encorafenib arm of part 2. The hazard ratio was 0.74 (0.60 to 0.92; two-sided P = .003) among patients treated with encorafenib plus binimetinib compared against patients treated with encorafenib in both parts 1 and 2. ORR by BIRC was 68% of patients treated with encorafenib plus binimetinib and 51% of patients treated with encorafenib in both parts 1 and 2.

Patients treated with encorafenib plus binimetinib had greater relative dose intensity and fewer grade grade 3/4 treatment related adverse events compared to patients treated with encorafenib alone.

“Together with part 1 results, these data confirm and extend the evidence for the contribution of binimetinib for the treatment of BRAF-mutant, advanced, unresectable melanoma,” concluded Dr Ascierto and coauthors. 

“This study confirms that a MEKi should be combined with a BRAFi in the treatment of patients with BRAFV600-mutant melanoma,” added associate editor of Journal of Clinical Oncology, Gary K. Schwartz, MD, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. 

Source: 

Ascierto PA, Dummer R, Gogas HJ, et al. Contribution of MEK inhibition to BRAF/MEK inhibitor combination treatment of BRAF-mutant melanoma: Part 2 of the randomized, open-label, phase III COLUMBUS trial. J Clin Oncol. Published online: July 28, 2023. doi: 10.1200/JCO.22.02322