Abstract 5195: Development of paired PDX-PDXO preclinical models for HER2-targeting ADC efficacy evaluation

Abstract Introduction: Tumor organoids replicate cancer lesions and capture tumor heterogeneity in vitro, and are invaluable for cancer drug development. Combining Patient-Derived Xenograft (PDX) models with corresponding Patient-Derived Xenograft Organoid (PDXO) models offers a comprehensive approach, enabling high-throughput, scalable in vitro data collection and providing insights into tumor behavior and drug responses in vivo. HER2 amplification is frequent in cancers like breast and gastric cancer, and HER2-targeted ADCs have shown exceptional efficacy. To support preclinical and mechanistic investigations that develop next-generation HER2-targeted ADCs and therapies, we established a preclinical panel of paired PDX-PDXO models with varying HER2 expression levels. Methods: Gastric (GA) and breast cancer (BR) PDXOs were generated from PDX tissue and authenticated by SNP assay. Morphology, histopathology, and genomic profiling were performed and compared with its corresponding PDX. ERBB2 expression and HER2 levels in PDX-PDXOs were detected by RNA sequencing and IHC. In vivo efficacy of 10 mpk DS8201 was studied in the PDXs, and in vitro IC50 was assessed in the PDXOs using CellTiterGlo (CTG) and High Content Imaging (HCI), allowing differentiation between cytostatic and cytotoxic responses. Correlation analysis of DS8201 response were performed based on the efficacy data from PDXOs and PDXs. Results: 34 GA and 24 BR PDXOs were developed from PDX tumors originally established from patients' biopsies. Hematoxylin-eosin (H&E) staining showed distinct features within PDXOs, similar to the corresponding PDXs. High correlation (>95%) in mutation and gene expression demonstrated that PDXOs largely preserve the genomic and transcriptomic features of the originating tumors. In vivo and in vitro efficacy studies of DS8201 were performed in 14 pairs of GA and BR PDX-PDXOs, among which 12 pairs display consistent HER2 IHC scores between PDX and PDXO. Overall, 6 out of 7 DS8201-sensitive PDXOs were also sensitive in PDXs and showed tumor regression, indicating high positive predictive value (PPV: 0.857) of PDXOs. The average TGI of PDXs classified for the corresponding PDXO as sensitive is much higher than TGI of PDXs classified for the corresponding PDXO as non-sensitive (97% vs. 69%, p=0.13). Besides, DS82001 sensitivity was observed in both HER+ and HER2- models, which might relate to the bystander effect of the payload and heterogeneity of PDX. Conclusion: The paired PDX-PDXO models were successfully established and provided a novel preclinical platform for investigating mechanisms of action (MOA) and resistance in patient-relevant models matched in both in vitro and in vivo stages for developing next-generation HER2-targeting therapies. Citation Format: Jinxi Wang, Jun Zhou, Limei Shang, Qingzhi Liu, Binchen Mao, Yi Sun, Peng Han, Lin Zhang, Likun Zhang, Xiaolong Tu, Wubin Qian, Peng Wang, Leilei Chen, Marten Hornsveld, Marrit Putker, Ludovic Bourre, Jingjing Wang. Development of paired PDX-PDXO preclinical models for HER2-targeting ADC efficacy evaluation [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 5195.