Clinical outcomes of pembrolizumab and enfortumab vedotin in variant histology urothelial carcinoma.

754 Background: Enfortumab vedotin (EV) in combination with pembrolizumab is an FDA-approved regimen for patients with locally advanced or metastatic urothelial carcinoma. However, its clinical benefit in the setting of variant histology remains uncertain. Methods: The Indiana University bladder cancer database was queried for patients diagnosed with variant histology treated with EV plus pembrolizumab between 2023 and 2025. Demographics, treatment line, metastatic sites, and histological variants were collected. We sought to evaluate clinical outcomes in patients with urothelial carcinoma harboring variant histology who received EV and pembrolizumab. Outcomes were stratified by degree of variant histology: ≥50% versus < 50% variant component on pathology. Kaplan-Meier estimates were used to evaluate progression-free survival (PFS) and overall survival (OS). The log rank test was used to compare groups. Results: A total of 32 patients were identified. Median age was 72 (range 49-89). EV plus pembrolizumab were administered as first-line therapy in 18 patients, second-line in 9, third-line in 4, and fourth-line in 1. Sites of metastasis included lymph nodes (n = 19), bone (n = 9), lung (n = 4), liver (n = 4), and adrenal glands (n = 2). Variant percentages were available for 26 patients; 10 demonstrated ≥50% variant histology. Common variants included squamous differentiation (n = 19), micropapillary (n = 9), plasmacytoid (n = 3), sarcomatoid (n = 1), pure squamous n = 1), and dedifferentiated urothelial carcinoma (n = 1). Six patients exhibited multiple variant patterns. Median follow-up was 10.1 months (range 1.6-20.3). Patients with ≥50% variant histology had a median PFS of 3.9 months (95% CI, 1.0-5.4), whereas those with < 50% variant component achieved a median PFS of 8.2 months (95% CI, 4.2-19.6) (p = 0.0355). For the entire cohort, median PFS was 5.8 months (95% CI, 4.3-15.5), median OS was 20.1 months (9.9-Not evaluable). Conclusions: EV combined with pembrolizumab demonstrated clinical activity in patients with variant histology urothelial carcinoma. Outcomes appeared more favorable in patients with a lower proportion of variant differentiation, suggesting that variant burden may influence response to therapy.