Background: For patients (pts) with advanced UC, pembro monotherapy has shown antitumor activity as first-line (1L) therapy in the phase 3 KEYNOTE-361 (NCT02853305) study of pembro ± platinum-based chemotherapy (chemo) vs platinum-based chemo and as second-line therapy in the phase 3 KEYNOTE-045 (NCT02256436) study of pembro vs investigator’s choice chemo. This exploratory analysis evaluated efficacy and safety of pembro monotherapy by UC histology in KEYNOTE-361 and KEYNOTE-045. Methods: KEYNOTE-361 enrolled pts with advanced UC and no prior systemic therapy; KEYNOTE-045 enrolled pts with advanced UC whose disease progressed or relapsed after 1L platinum-based chemo. Pure transitional cell (TC) and mixed predominant TC histology, as assessed by investigator, were allowed. Pembro monotherapy was given at a dose of 200 mg IV Q3W for up to 2 y or until disease progression, unacceptable toxicity, or withdrawal of consent in both studies. End points for this exploratory analysis were ORR, DOR, and PFS per RECIST v1.1 by central radiology assessment, and OS and safety in pts with pure TC or mixed predominant TC allocated to receive pembro monotherapy. Results: A total of 307 randomly assigned pts (280 [91.2%] pure TC histology; 27 [8.8%] mixed predominant TC histology) from KEYNOTE-361 and 268 pts (186 [69.4%] pure TC histology; 82 [30.6%] mixed predominant TC histology) from KEYNOTE-045 were included. Median follow-up for both studies was ≥32 mo. PFS, ORR, DOR, and OS for pembro were generally similar in pts with mixed predominant TC histology and pts with pure TC histology. In treated pts, grade 3-5 treatment-related AEs occurred at similar rates in KEYNOTE-361 (17.3% [48/277] pure TC; 18.5% [5/27] mixed predominant TC) and KEYNOTE-045 (16.9% [31/183] pure TC; 17.3% [14/81] mixed predominant TC). Conclusions: The observed clinical activity and safety profile of pembro monotherapy was generally consistent irrespective of histology in pts with UC in the KEYNOTE-361 and KEYNOTE-045 studies. Small sample size in some subgroups and limited data available to classify histology subgroups were limitations of this exploratory analysis. Clinical trial information: NCT02256436; NCT02853305.

NR, not reached. ^a+ indicates no PD at time of last disease assessment