Background: Inhibition of the MAPK pathway with dabrafenib (D) and trametinib (T) is efficacious in BRAF-mutant melanoma. MEK inhibitors have also shown activity in BRAF WT melanoma, particularly in NRAS-mutant tumors. However, most patients (pts) develop resistance to D and T. MEDI4736 (M), a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, has shown clinical activity with durable responses and an acceptable safety profile in multiple tumor types. Combined therapy with these agents may lead to enhanced durable tumor responses. Methods: A phase I, multicenter, open-label study (NCT02027961) evaluating the safety and efficacy of M at 3 or 10 mg/kg IV every 2 weeks (q2w) in combination with D 150 mg twice daily + T 2 mg daily, or T alone in pts with stage IIIc/IV melanoma. Pts enroll by BRAF status into dose escalation cohorts (3+3 design), followed by dose expansion: BRAF mutant in Cohort A (M+D+T); BRAF WT in Cohort B (M+T) or Cohort C (sequential T→M). Prior BRAF/MEK inhibitors were prohibited; prior immunotherapy was allowed, including anti-PD-1/anti-PD-L1 therapy. Results: As of December 5, 2014, 50 pts were treated. DLTs were observed in 1 pt in Cohort A1 (reversible grade [G] 3 thrombocytopenia) and 1 pt in Cohort B (reversible G3 choroidal effusion). No MTD was identified; M 10 mg/kg q2w was selected for expansion in all cohorts. The most frequent drug-related adverse events (AEs) by cohort were: pyrexia (63%) and fatigue (54%) (Cohort A); diarrhea (30%) and rash (25%) (Cohort B); and vomiting (67%) (Cohort C). 2 pts discontinued due to drug-related AEs (DLTs above). Clinical activity to date is shown below. Most responses are ongoing (range of duration: 0.1+ - 32+ wk). Conclusions: M can be combined with T ± D at full doses with a manageable safety profile, and evidence of clinical activity in BRAF-mutant and WT melanoma. Clinical trial information: NCT02027961

^aIncludes pts with ≥ 1 follow up scan or discontinuation due to PD or death prior to first scan (confirmed and unconfirmed CR/PR).