Background: Greater understanding of tumor immunology in melanoma has led to the development of targeted treatments with improved outcomes in patients (pts) with metastatic melanoma (MM). Dabrafenib, a V600E BRAF inhibitor, combined with trametinib, a MEK inhibitor, resulted in high response rates, progression-free survival (PFS) of 9.4 mo in BRAF mutation-positive melanoma and is now an FDA-approved combination. Adding an immunomodulator may further improve outcomes. MEDI4736, a highly potent anti-PD-L1 antibody, showed clinical activity in a phase 1 study of pts with solid tumors including MM and is being evaluated in combination with dabrafenib/trametinib or trametinib alone in BRAF mutation-positive or BRAFmutation-negative melanoma. Methods: This global, multicenter, open-label phase 1b study (NCT02027961) is enrolling adults with unresectable or MM and ECOG performance status 0-1 into 3 cohorts. In cohort A, BRAF V600E or V600K mutation-positive (BRAF-MP) pts receive dabrafenib orally (PO) twice daily, trametinib PO once daily (QD) and MEDI4736 intravenously (IV) every 2 wks (q2w), given concomitantly followed by continued dabrafenib/trametinib until progressive disease (PD). In cohorts B and C, BRAF V600E or V600K mutation-negative (BRAF-WT) pts receive trametinib PO QD and MEDI4736 IV q2w according to 2 different treatment schedules until PD. Primary objectives are determination of maximum tolerated dose (dose-limiting toxicity) and safety profile (adverse events, laboratory evaluations, physical exams, echocardiograms/electrocardiograms) of MEDI4736 in combination with dabrafenib/trametinib or trametinib alone. Secondary objectives include antitumor activity (objective response based on RECIST, duration of response, PFS, and overall survival), pharmacokinetic profile, and immunogenicity of the combination. Exploratory objectives include biomarkers, patient-reported outcomes, and tumor growth parameters. Recruitment is ongoing (target: 69 pts). Clinical trial information: NCT02027961.