Abstract 2961: AZD9592, an EGFR/cMET bispecific antibody-drug conjugate (ADC), demonstrates target-dependent efficacy in colorectal cancer (CRC) patient-derived xenograft (PDX) models

Abstract Background: AZD9592 is a bispecific ADC designed to target both epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition tyrosine kinase receptor (cMET), delivering a topoisomerase 1 inhibitor payload to tumor cells. Despite recent advances in ADC development for CRC, such as the use of trastuzumab deruxtecan to treat HER2-positive CRC, a significant unmet need remains for novel therapeutic approaches, particularly for patients with limited targeted treatment options. Methods: We evaluated the antitumor efficacy of AZD9592 and explored biomarker-response relationships in CRC PDX models across a range of very low to high EGFR expression (optical density of membrane [OD] 6.7-162.6) and cMET expression (OD 18.5-142.6) measured by immunohistochemistry-quantitative continuous score (IHC-QCS), as well as other molecular features like oncogene drivers. Responses were defined as ≥30% tumor volume reductions from baseline. Results: AZD9592 demonstrated dose-dependent efficacy, with responses observed in 34.5% of models at 8 mg/kg and 14.8% at 4 mg/kg. Biomarker analyses of tumors revealed a significant association between cMET expression levels by IHC-QCS and responses at 8 mg/kg. cMET levels were significantly higher in AZD9592-responsive models than in antibody-responsive and isotype control-responsive models (p<0.02 for both). An optimized cMET expression cutoff had a predictive performance with an area under the curve of 0.73. Compared to wildtype tumors, response rates were not significantly different in tumors harboring mutations in oncogenes that share signaling pathways with EGFR and cMET and where clinical activity of EGFR antibody therapies is limited, including KRAS and BRAF. Moreover, response rates were not significantly different across tumors derived from patients with or without prior irinotecan treatment, a chemotherapy that also inhibits topoisomerase I. Proteomics identified additional molecular features associated with response. Conclusions: AZD9592 demonstrated dose-dependent antitumor activity in CRC PDX models, including KRAS-mutant and KRAS-wildtype tumors. These responses suggest opportunities for clinical development of AZD9592 in CRC and the potential for biomarker-guided patient selection. Citation Format: Ying Zheng, Edward Rosfjord, Simon Christ, Stephanie Zalesak-Kravec, Italia Grenga, Fernanda Arnaldez, Frank Comer, Lara McGrath. AZD9592, an EGFR/cMET bispecific antibody-drug conjugate (ADC), demonstrates target-dependent efficacy in colorectal cancer (CRC) patient-derived xenograft (PDX) 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 2961.