Impact of histological subtypes in patients receiving first-line treatment with enfortumab vedotin/pembrolizumab in advanced metastatic urothelial cancer.

4575 Background: Metastatic urothelial carcinoma (mUC) represents a challenging clinical entity with significant morbidity and mortality. Enfortumab Vedotin plus Pembrolizumab (EV+P) has been established as an effective first-line (1L) treatment for mUC, but data regarding the impact of variant subtypes of UC remains limited. This study aims to describe the impact of different histological subtypes on mUC patients (pts) treated with 1L EV+P. Methods: This is a single-center retrospective cohort of pts with mUC treated with EV+P in first line between 6/1/2023 and 8/8/2024. Data were collected by chart review, including reviewed pathological reports and their impact on clinical outcomes (ORR, PFS, and OS). Four main histological groups were defined: 1)Transitional UC Predominant: Includes cases where transitional UC is the dominant component. 2) Transitional UC with <50% variant histologies of squamous or glandular differentiation. 3) Transitional UC with >50% variant histologies of squamous or glandular differentiation, including pure squamous or adenocarcinoma types. 4)Other Variant histologies: micropapillary vs. others (plasmacytoid, sarcomatoid, nested, and lipid-rich variants). Results: A total of 71 patients with mUC treated with first-line EV+P were included in this analysis, with a median age of 72.78 years. The median follow-up for the cohort was only 8 months (mos). The PFS rate at 12 mos was 43.28%, and the OS rate at 12 mos was 70%. Patients with predominant transitional UC (n=26) had a better response, with an ORR of 57.6% (15/26). Patients with UC having squamous or glandular differentiation (< or> 50%) showed inferior outcomes relative to all other subgroups. Specifically, patients with <50% squamous or glandular differentiation (n=6) had an ORR of 16.6% (1/6), while those with >50% (including pure squamous/glandular) (n=11) showed no response at all (0%, 0/11). Among the rest of the variants, only micropapillary (n=7) showed a substantial benefit with an ORR of 57.1% (4/7). Patients with other variant histologies, including sarcomatoid, plasmacytoid, nested, and lipid-rich (n=8), demonstrated inferior ORRs of 25% (2/8). ORRs based on different histologic subtypes are presented in Table. Conclusions: This analysis shows that histological subtypes significantly influence the treatment outcomes of Ev +P treatment. Favorable responses were observed in patients with predominant transitional histologies. Patients with mixed histologies containing squamous or glandular components showed poor responses to EVP independent of the cut-off > or < 50%, raising concern about the validity of the present cut-off value. Adequate responses were observed in the micropapillary subtype only. These findings emphasize the necessity for prospective validation and patient stratification of EV+P treatment in histological subtypes of UC. Alternative treatment strategies should be explored for patients with squamous or glandular subtypes. Transitional UC Predominant) n=37 Transitional UC <50% VH (squamous/glandular)n=6 Transitional UC >50% VH (squamous/glandular)n=13 Variant histologiesN=15 Other variant histologiesn=8 Micropapillary Variant n=7 ORR 57.6% (15/26) 16.6% (1/6) 0% (0/11) 25% (2/8) 57.1%(4/7)