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
Mar et al. (Sun,) studied this question.