Background: The interaction between programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2 represents a major pathway that tumors may use to evade immune control, enabling their survival and progression. Pembro, a highly selective and potent humanized monoclonal antibody that directly blocks PD-1, has demonstrated a manageable toxicity profile with durable responses in advanced melanoma. Inhibition of the MAPK pathway with a combination of BRAF and MEK inhibitors improves survival in BRAF^V600-mutant melanoma and may be synergistic with immunotherapies. KEYNOTE-022 (NCT02130466) is a multicenter phase 1/2 study of pembro in combination with D, a selective BRAF inhibitor, and T, a highly selective MEK1/2 inhibitor. In the randomized phase 2 study described here, we will evaluate the safety, tolerability, and preliminary efficacy of this triplet combination as first-line therapy for BRAF-mutant melanoma. Methods: Patients aged ≥ 18 y with histologically confirmed unresectable or metastatic stage III/IV BRAF^V600E/K- mutant melanoma and no prior therapy are to be randomized 1:1 to pembro 2 mg/kg IV Q3W with D 150 mg orally BID + T 2 mg orally daily or placebo + D + T. Randomization is to be stratified by ECOG PS (0 vs 1) and LDH level ( > 1.1× vs ≤ 1.1× ULN). Pembro is to be given for ≤ 24 mo or until confirmed disease progression, unacceptable toxicity, or pt or investigator withdrawal; pts experiencing confirmed complete response (CR) after ≥ 6 mo may discontinue pembro after receiving ≥ 2 doses beyond initial CR, but may continue treatment with D + T. AEs are to be graded by NCI CTCAE v4.0. Response is to be assessed at wk 12, then every 6 wk until mo 18, then every 12 wk thereafter by RECIST v1.1 per investigator. Primary end point is PFS; secondary end points are ORR, response duration, and OS. A data monitoring committee is to monitor safety and efficacy at a planned interim analysis (IA). Key end point for the IA is the 5-category ordinal response at wk 36 (CR, very good partial response [PR], moderate PR, stable disease, progressive disease) determined by central review. Recruitment in KEYNOTE-022 is ongoing; approximately 120 pts are expected to enroll. Clinical trial information: NCT02130466