Background: Treatment options are limited for patients (pts) with advanced urothelial cancer (UC) ineligible to receive cisplatin-based chemotherapy. Interim results from the first 100 pts enrolled in the phase 2, open-label KEYNOTE-052 (ClinicalTrials.gov, NCT02335424) study suggested first-line pembrolizumab (pembro) had antitumor activity and acceptable safety in this pt population. Results from the fully enrolled study are presented. Methods: Key eligibility criteria included age ≥ 18 y, advanced UC of the renal pelvis, ureter, bladder, or urethra, cisplatin ineligibility (ECOG PS 2, creatinine clearance ≥ 30 to < 60 mL/min, grade ≥ 2 neuropathy or hearing loss, NYHA Class 3 heart failure), no prior systemic chemotherapy for advanced UC, measurable disease per RECIST v1.1, ECOG PS 0-2, and provision of a tumor sample for biomarker analyses. Pembro 200 mg was administered every 3 wk. Imaging was performed at wk 9, then every 6 wk for the first year, and every 12 wk thereafter. The primary end point was confirmed overall response rate (ORR; RECIST v1.1, independent review). Efficacy data are presented for pts with ≥ 4 mo follow-up, and safety data are presented for all pts. Results: In total, 370 pts were enrolled; median age was 74 y (range, 34-94 y); 42% had an ECOG PS 2. Reasons for cisplatin ineligibility included ECOG PS 2 (32%), renal dysfunction (49%), and both ECOG PS 2 and renal dysfunction (10%). ORR (95% CI) was 27% (22%-32%) among pts with ≥ 4 mo follow-up (n = 307); 6% of pts achieved a complete response. Among the ≥ 4 mo follow-up group, median (range) time to response was 2.0 (1.6-4.8) mo; median (range) duration of response was not reached (1+ to 14+ mo). 78% of responders had a response for ≥ 6 mo (KM estimate). PFS and OS rates at 6 mo were 31% and 67%, respectively (KM estimate). Any grade and grade ≥ 3 drug-related AEs occurred in 229 (62%) and 58 (16%) pts. 19 (5%) pts discontinued treatment because of a drug-related AE. Conclusions: Results from the fully enrolled KEYNOTE-052 study confirm that pembro elicits clinically meaningful and durable responses in cisplatin-ineligible pts with UC, including elderly pts and those with poor performance status. Clinical trial information: NCT02335424