Treatment decision patterns post–enfortumab vedotin plus pembrolizumab in metastatic urothelial cancer.

e16562 Background: Enfortumab Vedotin plus Pembrolizumab (EV+P) is increasingly adopted as a first-line (1L) treatment for metastatic urothelial carcinoma (mUC). However, limited data are available on the optimal second line (2L) treatment following EV+P, particularly comparing platinum-based chemotherapy to targeted therapies in patients (pts) with actionable biomarker alterations This study retrospectively analyzes treatment patterns and outcomes of mUC pts treated at a single institution post-EV+P. Methods: A retrospective chart review was conducted to evaluate treatment patterns and outcomes in mUC pts receiving 1L EV+P. Data on clinical and genomic/biomarker characteristics, type of subsequent treatments, response evaluations, and survival were analyzed. Results: Between April 2023 and November 2024, 101 consecutive mUC pts treated with 1L EV+P were included. The median age was 74 years; 64.3% had visceral disease, and 16.8% had an ECOG performance status ≥ 2. The median number of EV+P cycles was 6. Among 85 evaluable pts, the overall response rate (ORR) was 63.5%. With a median follow-up of 7 months, the median progression-free survival (PFS) was 12 months (95% CI: 4.04–19.95), and 70.9% of pts were alive at 12 months. Overall survival (OS) data remain immature. Thirty pts developed disease progression; 26 (86.6%) received subsequent therapy, while 4 received best supportive care only. Treatment decisions were made at the physician's discretion. Among the 26 pts, 13 (50%) had actionable biomarker alterations (e.g., HER2 IHC3+, FGFR mut/fusions). Nine of these pts received targeted therapies, and 4 received other treatments, including platinum-based chemotherapy. In the 13 pts without actionable biomarkers, 9 (69.2%) received platinum-based chemotherapy, while 4 received other systemic therapies. In second line setting, stable disease or better was observed in 66.6% of pts receiving targeted therapies and 54.5% receiving platinum-based chemotherapy. Early disease progression occurred in 4 of 11 pts treated with platinum-based chemotherapy, including 1 with a HER2 IHC3+, whereas no early progression was observed in pts receiving targeted therapies. Notably, 3 pts in the targeted therapy group received third-line therapy, compared to none who received 2L platinum-therapy. Conclusions: Our results demonstrate that early outcomes from 1L EV+P are comparable to EV-302. In the 2L setting, targeted therapies, if available, were preferred over platinum-based chemotherapy and demonstrated a rate of clinical benefit. Our findings underscore the need for prospective trials to evaluate optimal sequencing strategies for pts with mUC, specifically with those where targeted therapy is an option.