Abstract 5980: Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in digestive cancer

Abstract Context: Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data, we explore the use of large PDOs collections to characterize ADC efficacy and affinity with the targeted cells through systematic mapping of the relationship between target antigen abundance and payload efficacy. Methods: We have assembled a matched collection of PDOs and transcriptomic data from 135 colorectal (CRC) and pancreatic (PDAC) cancer patients, generated from primary tumour samples and metastatic biopsies. Patients ranged from 31 to 89 years old and had experienced an average of 2.6 lines of treatment prior to the PDO-generating tissue sampling. We used gene expression levels of well-known target antigens such as CEACAM5, HER2, and TROP2 as proxies for protein expression. This data is combined with PDO responses to microtubule and topoisomerase inhibitors, thereby enabling us to explore the relationship between target antigen abundance and payload efficacy. This allows us to generate data-driven hypothesis that were then validated in vitro on a pool of CRC and PDAC PDOs. Results: We identify patient subgroups by combining the RNA expression level and payload efficacy for ADCs against HER2 and CEACAM5. We systematically matched the RNA expression levels and histology for the corresponding proteins. Then we confirmed the response of the PDOs extracted from the tumors of these patients in vitro. We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC and PDAC. Citation Format: Lélia Polit, Gizem Altay, Mia Cabantous, Anna-Rose Gryspeert, Jérome Cartry, Jacques RR. Mathieu, Sabrina Bedja, Alice Boileve, Michel Ducreux, Sophie Postel-Vinay, Fanny Jaulin, Gustave Ronteix. Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in digestive cancer [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 5980.