Background: A, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, inhibits PD-L1/programmed death-1 (PD-1) and PD-L1/B7.1 binding and shows promising clinical activity in patients (pts) with cutaneous mel (objective response rate [ORR] 33%; median progression-free survival [mPFS] 5.5 months; Hodi et al SMR 2014). C promotes intratumoral T-cell infiltration, major histocompatibility complex 1 upregulation, and PD-L1 expression via targeted MEK inhibition in preclinical models (Ebert et al Immunity 2016) and tumor biopsy specimens (Bendell et al ASCO 2016). Therefore, clinical benefits may be enhanced by combining A + C vs A. This Phase Ib dose-escalation and -expansion study (NCT01988896) suggested higher ORR/disease control rate (DCR, ORR + stable disease) and longer PFS may be achieved with A + C vs A or C alone in mel. We present updated safety and efficacy data. Methods: Oral C, escalated 20 mg→40 mg→60 mg, was given qd for 21 days followed by 7 days off. Intravenous (IV) A was given at 800 mg q2w. Tumor-specific expansion cohorts were enrolled at maximum tolerated doses (C 60 mg/d 21/7; A 800 mg IV q2w). No prior anti–PD-L1 or –PD-1 therapy was allowed. Results: Data cut-off was Oct 12, 2016; 22 patients were safety-evaluable (two ocular, 20 non-ocular [ten each BRAF-mutant and -wild-type]). Median safety follow-up was 14.4 months (range 2.1–23.2). Adverse events (AEs) were experienced in all pts (diarrhea [20 pts, 90.9%] and rash [15 pts, 68.2%] were most common); related grade (G)3–4 AEs in 54.5% (diarrhea [three pts, 13.6%] and dermatitis acneiform [two pts, 9.1%] were most common; no related G5 AEs); related serious AEs in 13.6%. All were manageable. One pt discontinued A + C due to an AE. RECIST v1.1-confirmed ORR was 45.0% in pts with non-ocular mel (median duration of response was not reached); DCR was 75.0%; mPFS was 12.0 months (95% CI 2.8–not evaluable). ORR was similar for pts with BRAF-mutant and wild-type mel. Conclusions: Updated results confirm previous findings that suggest higher ORR/DCR and longer PFS may be achieved with A + C vs A or C monotherapy for mel. Together with biomarker data from other cohorts, our data suggest that the immune contexture may be altered by C, enhancing A activity. Clinical trial information: NCT01988896