Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report updated safety and efficacy associated with avelumab as a 2^nd-line therapy in patients (pts) with metastatic urothelial carcinoma (mUC; NCT01772004). Methods: Pts with mUC unselected for PD-L1 expression received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by IHC. Results: As of Oct 7, 2015, 44 pts (27 [61.4%] with visceral metastasis) were treated with avelumab (median 14 wks [range 2-56]) and followed for a median of 11 mos (range 10-13). Median age was 68 y (range 30-84), ECOG PS was 0 (43.2%) or 1 (56.8%), and median number of prior therapies was 2 (range 1-6). Treatment-related (TR) AEs occurred in 30 pts (68.2%); the most common (≥10%) were infusion-related reaction (20.5%), fatigue (20.5%), asthenia (11.4%), and nausea (11.4%). Grade ≥3 TRAEs were asthenia, myositis, decreased appetite, and elevated CPK or AST (each 1 event) and no treatment-related deaths occurred. ORR was 18.2% (8 pts; 95% CI: 8.2, 32.7) with 2 CRs and 6 PRs; 4 were ongoing. SD was observed in 17 pts (38.6%); disease-control rate was 56.8%. PD-L1 expression was evaluable in 35 pts. Using a ≥5% cutoff for tumor cell staining, 12/35 [34.3%] were PD-L1+; ORR was 50.0% in PD-L1+ pts (6/12; 95% CI: 21.1, 78.9) vs 4.3% in PD-L1- pts (1/23; 95% CI: 0.1, 21.9). PFS rate at 24 wks was 58.3% (95% CI: 27.0, 80.1) in PD-L1+ pts vs 16.6% (95% CI: 4.2, 36.0) in PD-L1-. ORR in pts +/- baseline visceral metastasis was 18.5% (5/27) and 17.6% (3/17), respectively. OS at 12 mos was 50.9% (95% CI: 32.6, 66.6) for the overall population. Conclusions: Avelumab showed an acceptable safety profile and promising clinical activity in pts with mUC. Greater activity in pts with PD-L1+ tumors was observed. A randomized phase 3 trial of avelumab in pts with mUC is underway. *Proposed INN. Clinical trial information: NCT01772004