PURPOSE: In COLUMBUS part 1, patients with advanced BRAFV600-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 a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US 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. METHODS: In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. RESULTS: Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2 months (7.4 to 11.1) for ENCO300 (parts 1 and 2) and 7.4 months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1 and 2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1 and 2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. CONCLUSION: COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

• MeSH
• Protein Kinase Inhibitors adverse effects   therapeutic use   MeSH
• Humans MeSH
• Melanoma * drug therapy   genetics   MeSH
• Mitogen-Activated Protein Kinase Kinases MeSH
• Mutation MeSH
• Skin Neoplasms * drug therapy   genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Vemurafenib adverse effects   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• encorafenib MeSH Browser
• Protein Kinase Inhibitors MeSH
• Mitogen-Activated Protein Kinase Kinases MeSH
• Proto-Oncogene Proteins B-raf MeSH
• Vemurafenib MeSH

PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

• MeSH
• Double-Blind Method MeSH
• Humans MeSH
• Herpesvirus 1, Human * MeSH
• Melanoma * drug therapy   MeSH
• Oncolytic Virotherapy * methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• pembrolizumab MeSH Browser
• talimogene laherparepvec MeSH Browser