Abstract 5950: Assessment of response and overall survival (OS) for various systemic therapies in <i>ERBB2</i>-altered advanced urothelial carcinoma (aUC)

Abstract Background: A subset of aUCs harbor ERBB2 alterations. While anti-HER2 therapies in HER2-over-expressing aUC have been promising, relationships between ERBB2 alterations and response to other systemic therapies are unclear. Based on available data, we hypothesized that ERBB2-altered aUC would respond less favorably to immune checkpoint inhibitor (ICI), enfortumab vedotin (EV), and sacituzumab govitecan (SG) than ERBB2-wildtype aUC. Methods: This single-center retrospective study included patients (pts) diagnosed with aUC between 5/6/2016 and 9/23/2022 who underwent panel-based somatic tumor sequencing (120 tissue-based, 9 ctDNA) and received ICI, EV, or SG in first line (1L) or as salvage (2L+). Pts were grouped as ERBB2alt aUC, including tumors harboring ERBB2 amplification (n=13) and/or ERBB2 mutation (n=9), and ERBB2-wildtype(wt) aUC (n=107). Observed response rate (ORR) and OS measured from each therapy start were evaluated. Kaplan-Meier method was used to calculate OS curves. Log-rank and Fisher’s exact tests were used to compare OS and ORR between groups, respectively. Results: 129 pts were evaluable for ERBB2 status; 22 (17%) were ERBB2alt. Baseline characteristics including age, sex, prior extirpative surgery rate, ECOG performance status, proportion of pts with liver metastases, and presence of de novo metastasis were similar between groups. One pt with ERBB2alt aUC received 1L EV; none received 1L SG. Results are shown in Table 1. Conclusions: In pts receiving 2L+ ICI, significantly higher ORR and longer OS were noted in pts with ERBB2alt vs ERBB2wt aUC, contrary to our hypothesis; ERBB2alt was also associated with higher ORR to 2L+ EV. Limitations include retrospective design, limited sample size and power for subsets, lack of randomization, selection/confounding biases, and lack of HER2 protein IHC assessment. Results are hypothesis-generating and need external validation. Citation Format: Jacob B. Leary, Thomas L. Enright, Dimitra Rafailia Bakaloudi, Rafee Talukder, Michael T. Schweizer, Jessica E. Hawley, Bruce Montgomery, Evan Y. Yu, Andrew C. Hsieh, Todd A. Yezefski, Petros Grivas, Ali Raza Khaki, Ruben Raychaudhuri. Assessment of response and overall survival (OS) for various systemic therapies in ERBB2-altered advanced urothelial carcinoma (aUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5950.