Clinical and genomic characteristics of advanced urothelial carcinoma (UC) patients (pts) who fail therapy with enfortumab vedodin (EV) plus pembrolizumab (P).

685 Background: EV plus P has become the standard-of-care first-line therapy for most pts with advanced UC in the United States, based on results of the EV-302 study. However, primary progressive disease was noted in 8.7% of pts and median PFS was 12.5 months (mos) in the EV plus P treated pts on EV-302. Pts who fail to respond to EV plus P therapy or quickly lose response have a poor prognosis, highlighting the need for early identification of this pt cohort. Methods: This is a retrospective analysis of advanced UC pts, who initiated EV plus P at 5 academic institutions from 8/13/2018 to 7/21/2025. All pts had somatic next generation sequencing of their tumor tissue performed using a commercially available assay. Pts also needed to have at least 1 whole body scan to assess for treatment response, which was interpreted using RECIST criteria by the treating physician. Pts who had primary progressive disease or lost response to EV plus P within 6 mos of starting therapy were selected for this analysis. Extracted data included demographic, clinical, treatment, and genomic variables. Data was analyzed using descriptive statistics and Kaplan-Meier estimation. Results: A total of 29 were included, with 69% being male, 79.0% identifying as Caucasian, and a median age of 67 years [range, 27 to 92]. 76% had a primary bladder tumor, 20.6% had a primary upper tract tumor, and 3.4% had primary urethral tumor. At EV plus P start,14% had liver metastasis and 7.8% had peritoneal metastasis. Median duration of P therapy was 3.0 mos [range, 1.0 to 33.0], while median duration of EV therapy was 2.4 mos [range, 0.3 to 5.1]. Median progression free survival (mPFS) was 3.4 mos [IQR, 2.1 to 7.8], while median overall survival (mOS) was 12.0 mos [IQR, 8.3 to 24.0]. Median time to next therapy from EV plus P start, available in 25 pts, was 5.4 mos [range, 2.5 to 24.2]. Median tumor mutational burden (TMB) was 8 m/MB [range, 1 to 71] (available for 25/29 pts). Microsatellite instability (MSI) high status was 3.4% (available for 29/29 pts). HER2 immunohistochemistry (IHC) expression of 1+ or higher was noted in 86% tumor samples (available for 14/29 pts). HER2 positivity by fluorescence in situ hybridization (FISH) was positive in 21% of samples (available for 17/29 pts). Selected genomic alterations for all pts are listed in Table 1. Conclusions: This small retrospective dataset demonstrated a poor mPFS and mOS in pts with advanced UC who have primary progressive disease or loss of response within 6 mos to first-line EV plus P therapy. Low TMB/MSI-high status as well as frequent TERT variant promoter and FGFR2/3 alterations were noted. Further investigation into the genomic landscape of these tumors is needed. Selected genomic alterations of pts who fail EV plus P therapy. Genomic mutation % of pts FGFR 2/3 41 MTAP 6.7 TERT variant promoter 62 ERBB2 17 CDKN2A/2B 11