Background: There is much interest in determining how to incorporate BRAF inhibitors with immune checkpoint inhibitors in the treatment of patients (pts) with BRAF-mutant MM. A phase I study showed that concurrent administration of IPI, an antibody that blocks cytotoxic T-lymphocyte antigen-4, and VEM, an inhibitor of BRAF V600-mutated kinase, caused significant dose-limiting hepatotoxicity in BRAF-mutant MM pts. An alternate strategy is to use these agents sequentially in order to minimize toxicities observed with concurrent administration and to improve efficacy over either agent alone. Methods: This single-arm, open-label, phase II study evaluated the safety of VEM followed by IPI in treatment-naïve MM pts harboring a BRAF V600 mutation. Pts initially received VEM for 6 weeks (960 mg twice daily) followed by IPI at 10 mg/kg (Q3W x 4 doses, then Q12W beginning at week 24 until disease progression or unacceptable toxicity) [VEM1-IPI phase]; VEM was then restarted. The primary objective was to estimate the incidence of grade 3–4 drug-related skin adverse events (AEs) during the VEM1-IPI phase. Results: Among 46 pts treated in the VEM1-IPI phase, 80% were male, 52% had stage M1c, and 54% had ≥ 5 sites involved. Grade 3–4 drug-related skin AEs occurred in 15 (33%) pts during the VEM1-IPI phase, the most common of which was rash in 9 (20%) pts. Grade 3–4 drug-related gastrointestinal AEs occurred in 10 (22%) pts (diarrhea in 5 [11%]) and hepatobiliary AEs in 2 (4%) pts (hepatitis; hyperbilirubinemia). There were no deaths due to study drug toxicity. At a median follow-up of 10.5 mo, the objective response rate was 30% (95% CI, 18%–46%) during the VEM1-IPI phase. Median progression-free survival was 4.4 mo (95% CI, 4.2–5.9). Interim median overall survival was 20.3 mo (95% CI, 11.1–NE). Conclusions: VEM followed by IPI at 10 mg/kg has a manageable safety profile with no significant signals of hepatobiliary toxicity, as seen with concurrent VEM and IPI; the incidence of grade 3–4 skin AEs was higher than with either agent alone. The benefit/risk of this sequence needs to be evaluated further based on individual patient characteristics and new treatment options. Clinical trial information: NCT01673854