Results of COLUMBUS Part 2: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus ENCO in BRAF-mutant melanoma

Abstract

Background: The addition of a MEK inhibitor (MEKi) to a BRAF inhibitor (BRAFi) in BRAF V600‐mutant metastatic melanoma improves efficacy, including progressionfree survival (PFS) and objective response rate (ORR), and attenuates some BRAFi‐associated toxicities. Part 1 of the COLUMBUS study met its primary endpoint. The BRAFi ENCO 450 mg once daily (QD)+the MEKi BINI 45 mg twice daily (BID; COMBO450) improved PFS vs vemurafenib (VEM) alone and ENCO 300 mg QD (ENCO300) alone in patients (pts) with advanced BRAF V600‐mutant melanoma. The tolerability of COMBO450 was favorable compared with VEM or ENCO300. In Part 2, the contribution of BINI to the combination was further evaluated by maintaining the same dose of ENCO in the combination (ENCO 300 mg QD +BINI 45 mg BID; COMBO300) and comparator arms (ENCO300 alone; ClinicalTrials.gov, NCT01909453; EudraCT, 2013‐001176‐38). Methods: Pts were randomized 3:1 to COMBO300 or ENCO300. Data from ENCO300 arms in Parts 1+2 were combined for the primary efficacy comparison of PFS by independent blinded central review (BCR). Other analyses included PFS for COMBO300 vs ENCO300 (Part 2 only), ORR, complete response (CR) and partial response (PR) by BCR and local review, and safety. Results: Pt characteristics are presented in the Table. Median PFS (95% CI) for COMBO300 was 12.9 mo (10.1‐14.0) vs 9.2 mo (7.4‐11.0) for ENCO300 (Parts 1+2) and 7.4 mo (5.6‐9.2) for ENCO300 (Part 2). The hazard ratio (HR) for COMBO300 was 0.77 (0.61‐0.97; P=0.029, 2‐sided) vs ENCO300 (Parts 1+2) and 0.57 (0.41‐ 0.78; P<0.001, 2‐sided) vs ENCO300 (Part 2). ORR, CR, and PR by BCR/local review (%) were 66/72, 8/11, and 58/62 for COMBO300, 50/56, 5/8, and 45/49 for ENCO300 (Parts 1+2), and 50/53, 3/3, and 47/50 for ENCO300 (Part 2). Safety profiles were consistent with Part 1 (Table). Conclusions: COMBO300 meaningfully improved PFS, ORR, and tolerability vs ENCO300, confirming the contribution of BINI to both efficacy and safety. (Table Presented).