Background: First-line treatment with pembrolizumab (pembro) monotherapy has shown durable clinical activity in selected patients (pts) with advanced/unresectable or metastatic urothelial carcinoma (UC). In a pooled population of pts with advanced UC from the single-arm phase 2 KEYNOTE-052 (NCT02335424) and the randomized, open-label, phase 3 KEYNOTE-361 (NCT02853305) studies, this exploratory analysis evaluated the relationship between baseline characteristics and clinical outcomes of first-line pembro monotherapy. Methods: Cisplatin-ineligible pts with advanced UC were enrolled in KEYNOTE-052 and chemotherapy-naive pts with advanced UC were enrolled in KEYNOTE-361. For analysis of predictive factors for ORR and OS in pembro-treated pts, the purposeful selection method was used to build the multivariable logistic regression model (ORR) and multivariable Cox model (OS), beginning with a univariable analysis of each independent variable. Any variable in the univariate model with P < 0.10 was a candidate for the multivariate model. The stepwise selection method was used to select the variables in the final model. Significance of the final model was set at P< 0.05. Data cutoff dates were September 26, 2020 (KEYNOTE-052) and April 29, 2020 (KEYNOTE-361). Results: This pooled analysis included 681 pts treated with pembro monotherapy (KEYNOTE-052, N = 374; KEYNOTE-361, N = 307 [170 were cisplatin ineligible]). Median follow-up was 51.9 mo (range, 22.0-65.3). ORR was 29.4% (95% CI, 26.0-32.9; 69 CRs, 131 PRs), and median DOR was 33.2 mo (range, 1.4+ to 60.7+). Median OS was 12.5 mo (95% CI, 11.0-14.6). By multivariate analysis, independent factors significantly associated with higher ORR were PD-L1 status (combined positive score [CPS] ≥10 vs CPS < 10; odds ratio [OR], 1.90 [95% CI, 1.33-2.71]; P = 0.0004), site of metastasis (lymph node only vs visceral disease; OR, 1.66 [95% CI, 1.06-2.59]; P = 0.0265), liver involvement (absent vs present; OR, 1.75 [95% CI, 1.06-2.89]; P = 0.0294), and baseline hemoglobin level ≥10 vs < 10 g/dL; OR, 2.17 [95% CI, 1.09-4.31]; P = 0.0276). Multivariate analysis of OS is displayed in the Table. Conclusions: This exploratory multivariate analysis identified numerous factors, including PD-L1–positive status (CPS ≥10), lymph node only metastasis, and lower ECOG PS score, associated with improved clinical outcomes in pts with advanced UC treated with first-line pembro monotherapy. Clinical trial information: NCT02335424 and NCT02853305.