Abstract 5189: Exploring the clinical utility of HER2-targeted antibody-drug conjugate in urothelial carcinoma using patient-derived models

Introduction. The FDA granted accelerated approval for trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate (ADC), for the treatment of patients with advanced solid tumors with HER2 3+. However, the role of HER2 in bladder cancer pathogenesis and its utility as a therapeutic target for this disease remains unclear. Here, we characterized a growing biobank of patient-derived organoid (PDO) and xenograft (PDX) models for HER2-targeted kinase inhibitor and ADC sensitivity, with the goal of guiding future therapeutic strategies for patients with bladder cancer. Methods. We generated and characterized the mutational status and HER2 expression levels of 19 urothelial cancer PDOs and 34 PDXs. A subset of these models was further characterized using a multiplatform approach, including single-cell DNA and RNA seq. We leveraged these models to study the biologic determinants of PDX sensitivity to neratinib and T-DXd. We also studied sensitivity to T-DXd, as well as to its cytotoxic payloads (exatecan) in vitro using paired PDO models. To understand the real-world clinical outcomes of T-DXd in metastatic urothelial carcinoma, we analyzed 28 patients treated with T-DXd at Memorial Sloan Kettering to evaluate the therapeutic outcomes and to identify potential biomarkers of sensitivity to HER2-targeted therapies. Results. Single-cell RNA and DNA seq analysis of 4 PDOs demonstrated high interpatient and intratumoral heterogeneity of HER2 expression and ERBB2 copy number. Our bladder cancer PDX models also demonstrated greater sensitivity to T-DXd than neratinib, consistent with clinical data in bladder cancer patients. Sensitivity to exatecan, as measured by inhibition of cell proliferation and induction of apoptosis, was more predictive of T-DXd sensitivity than HER2 expression level. 3 patients remained on the treatment for more than 1 year, all of whom had an IHC score of HER2 3+ and ERBB2 amplification, suggesting HER2 3+ and ERBB2 amplification are predictive of but not required for clinical benefit with T-DXd. Conclusion. Multi-omic single-cell analysis demonstrated significant interpatient and intratumor heterogeneity of HER2 expression and ERBB2 copy number gain. Sensitivity to the T-DXd payload was more predictive of PDX response than HER2 expression levels, with significant tumor regression observed with T-DXd in models with low HER2 expression. Our data suggest that clinical trials of HER2-targeted ADCs should not be restricted to patients with HER2 overexpression and that novel biomarkers will be needed to identify those urothelial cancer patients most likely to benefit from FDA-approved and investigational ADCs. Real-world data from metastatic urothelial carcinoma patients treated with T-DXd suggested that HER2 3+ and ERBB2 amplification are associated with exceptional response to T-DXd treatment. Citation Format: Xinran Tang, Ziyu Chen, Jasmine Thomas, Karan Nagar, John Christin, Sizhi Gao, Jiaqian Luo, Elisa de Stanchina, Jonathan A. Coleman, Michael M. Shen, Hikmat Al-Ahmadie, Gopa Iyer, Kwanghee Kim, David B. Solit. Exploring the clinical utility of HER2-targeted antibody-drug conjugate in urothelial carcinoma using patient-derived models [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 5189.