Background: Pembro monotherapy is a standard of care for advanced urothelial carcinoma (UC) and showed antitumor activity and acceptable safety when combined with lenva in the phase 1b/2 KEYNOTE-146 study. We present results of LEAP-011 (NCT03898180), a randomized, double-blind, multicenter, global, phase 3 study of first-line pembro + lenva vs pembro + placebo in pts with locally advanced or metastatic UC who are cisplatin-ineligible with PD-L1–positive tumors or are ineligible to receive platinum-based chemotherapy. Methods: Adults with histologically confirmed, locally advanced/unresectable or metastatic UC who were cisplatin-ineligible with tumors expressing PD-L1 (combined positive score ≥10) or were ineligible to receive platinum-based chemotherapy regardless of PD-L1 status were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 cycles (̃2 y) + either lenva 20 mg orally once daily or placebo. Primary end points were PFS per RECIST v1.1 and OS. The key secondary end point was ORR per RECIST v1.1. An independent data monitoring committee (DMC) regularly reviewed safety data every 3 months; for the 6th review, a nonbinding futility analysis to evaluate ORR (−1%) and PFS (HR ≥1.1) was performed. There was no futility bound for OS. Results: Of 441 randomly assigned pts, 218 were assigned to receive pembro + lenva (median age, 74 y [range, 43-93]; ECOG PS 2, 83.5%) and 223 (median age, 73 y [range, 47-92]; ECOG PS 2, 83.0%) were assigned to receive pembro + placebo. Median duration of treatment was 3.8 mo (range, 0.0-20.7) for pembro + lenva and 3.4 mo (range, 0.0-22.0) for pembro + placebo. Median PFS was 4.2 mo (95% CI, 3.8-5.9) in the pembro + lenva group and 4.0 mo (95% CI, 2.7-5.4) in the pembro + placebo group (HR, 0.91 [95% CI, 0.71-1.16]). Median OS was 11.2 mo (95% CI, 7.4-14.9) with pembro + lenva vs 13.8 mo (95% CI, 9.8-18.8) with pembro + placebo (HR, 1.25 [95% CI, 0.94-1.67]; 6-mo OS rate, 63.6% vs 70.7%). ORR was 31.2% with pembro + lenva vs 26.5% with pembro + placebo. In 436 treated pts, treatment-related AEs (TRAEs) occurred in 186 of 214 pts (86.9%) in the pembro + lenva group and in 149 of 222 pts (67.1%) in the pembro + placebo group. Grade 3-5 TRAEs occurred in 107 pts (50.0%) in the pembro + lenva group and in 62 pts (27.9%) in the pembro + placebo group. Death from a TRAE occurred in 6 pts (2.8%) in the pembro + lenva group and in 1 pt (0.5%) in the pembro + placebo group. Conclusions: The safety profile of pembro + lenva was consistent with that of previous studies; no new safety signals were observed. The benefit/risk ratio for pembro + lenva was not considered positive vs pembro + placebo in platinum-ineligible pts with advanced UC. Antitumor activity of pembro + placebo was similar to what has been reported in previous studies, and pembro monotherapy remains standard of care as first-line therapy in platinum-ineligible pts with advanced UC. Clinical trial information: NCT03898180.