BackgroundBRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3.

Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022.

Table 1.

Study treatments and end points

Phase 3
Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro 
Primary PFS (RP3D vs control; by BICR) 
Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics 
Phase 3
Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro 
Primary PFS (RP3D vs control; by BICR) 
Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics 

BICR, blinded independent central review; OS, overall survival.

Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.