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Background: BRAF inhibitors plus MEK inhibitors (BRAFi/MEKi) and immune checkpoint inhibitors (CPIs) are approved for BRAF V600-mutant advanced melanoma. Combinations of BRAFi/MEKi with CPIs may further improve outcomes and could offer additional treatment strategies., Methods: STARBOARD (NCT04657991) is a phase III study with an initial safety lead-in (SLI) phase conducted to determine the recommended phase III dose (RP3D) for encorafenib in combination with binimetinib and pembrolizumab. Patients with untreated, unresectable locally advanced or metastatic BRAF V600E/K-mutant cutaneous melanoma received binimetinib 45 mg twice daily and pembrolizumab 200 mg every 3 weeks plus encorafenib 450 mg once daily (COMBO450 plus pembrolizumab) or 300 mg once daily (COMBO300 plus pembrolizumab). The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety, objective response, time to response, and duration of response. Progression-free survival was assessed post hoc., Results: In the SLI, the median follow-up duration was 19.4 months. Twenty patients received COMBO450 plus pembrolizumab and 17 received COMBO300 plus pembrolizumab. DLTs occurred in 1 of 17 DLT-evaluable patients in the COMBO450 plus pembrolizumab arm and in 2 of 17 DLT-evaluable patients in the COMBO300 plus pembrolizumab arm. No treatment-related deaths occurred in either treatment arm. The overall response rate was 65.0 % in the COMBO450 plus pembrolizumab arm and 47.1 % in the COMBO300 plus pembrolizumab arm., Conclusion: The STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Oleksandr Dudnichenko: No disclosures or conflicts of interest to report. Oleksandr Dudnichenko. No disclosures or conflicts of interest to report. Konstantin Penkov. Honoraria: AstraZeneca, Merck Sharp & Dohme, Nektar, Pfizer, Regeneron Pharmaceuticals, Inc., Roche. Meredith McKean. Research Funding: Ascentage Pharma Group, Alpine Immune, Arcus Biosciences, Arvinas, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, Genentech, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmViraPharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kinnate Biopharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar Therapeutics, Novartis, Oncorus, PACT Pharma, Pfizer, Plexxikon, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seagen, Synthrox, Tempest Therapeutics, TeneoBio, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences. Consulting or Advisory Role: Array BioPharma, Astellas Pharma, AstraZeneca, BicycleTx Limited, Castle Biosciences, IDEAYA Biosciences, iTeos, Therapeutics, MedPage Today, Pfizer, Regeneron. Mario Mandalà. Honoraria: MSD Oncology, Novartis, Pierre Fabre, Sanofi/Aventis, Bristol Myers Squibb/Sanofi. Consulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre. Research Funding: Novartis (Inst). Mariia Kukushkina. No disclosures or conflicts of interest to report. Timothy Panella. No disclosures or conflicts of interest to report. Tibor Csőszi. No disclosures or conflicts of interest to report. Paola Gerletti. Employment: Formerly Pfizer. Mahgull Thakur. Employment: Formerly Pfizer. Anna Polli. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Alessandra di Pietro. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Dirk Schadendorf. Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, Replimune. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, MSD, Pierre Fabre, Sanofi/Regeneron., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)