Abstract 2957: Establishing preclinical activity of topoisomerase I inhibitor (TOPO1i) antibody-drug conjugate AZD9592 in patient-derived xenograft (PDX) models of metastatic colorectal cancer (mCRC) in context of irinotecan pretreatment and resistan

Abstract Background: Each year an estimated 1.9 million people are diagnosed with colorectal cancer worldwide and approximately 930, 000 people die due to mCRC. The TOPO1i irinotecan is used frequently in combination chemotherapy regimens to treat mCRC that cannot be managed with surgery. Colorectal tumor cells often overexpress the cell membrane proteins epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition tyrosine kinase receptor (cMET). Overexpression of either EGFR or cMET is associated with cancer progression and poor clinical prognosis in mCRC. AZD9592 is a bispecific antibody-drug conjugate that binds EGFR and cMET and delivers a TOPO1i payload. Methods: We evaluated a set of 9 colorectal PDX models with a broad range of EGFR and cMET protein expression. Eight of these models were mCRC obtained from tumors biopsied from the liver (n=7) or lung (n=1). We evaluated these models for a response to AZD9592 (administered in a single dose at 2, 4, or 8 mg/kg), irinotecan, or irinotecan plus oxaliplatin. We also examined whether AZD9592 induced responses in PDX models with tumors that progressed after irinotecan treatment. A response was defined as ≥30% tumor volume reduction from baseline. Results: A single dose of AZD9592 resulted in responses in 100% (9/9) of tumors treated with 8 mg/kg, 67% (6/9) of tumors treated with 4 mg/kg, and 33% (3/9) of tumors treated with 2 mg/kg. A single dose of irinotecan resulted in a response in 33% (3/9) of tumors. Irinotecan plus oxaliplatin resulted in a response in 55% (5/9) of tumors. Subsequent dosing with AZD9592 was feasible in 4 of the PDX models that did not respond to irinotecan; responses to a single dose of AZD9592 were observed in 50% (2/4) and 75% (3/4) of these models treated with 4 or 8 mg/kg, respectively. A similar experiment was conducted in 2 of the 4 models that did not respond to irinotecan plus oxaliplatin; a response was observed in 1 of these models with subsequent AZD9592 dosing at both 4 and 8 mg/kg. We also evaluated the effect of multiple doses of AZD9592 on the magnitude and duration of response. In 22% of mCRC PDX models (2/9), multiple doses of AZD9592 increased the magnitude of response at 4 mg/kg compared to a single dose. In 78% of models (7/9), multiple doses of AZD9592 4 mg/kg increased the duration of response. Dosing AZD9592 every 3 weeks improved the magnitude of response in some models and increased the time until tumor relapse. Conclusions: AZD9592 was effective in mCRC PDX models, even at the lowest doses tested. AZD9592 was effective in mCRC PDX models that did not respond to irinotecan-based treatment. Ongoing research is evaluating whether multiple doses of AZD9592 can induce resistance in PDX models, and potential resistance mechanisms are being assessed by molecular characterization. Citation Format: Mel Ehudin, Lara McGrath, Simon Christ, Italia Grenga, Fernanda Arnaldez, Frank Comer, Edward Rosfjord. Establishing preclinical activity of topoisomerase I inhibitor (TOPO1i) antibody-drug conjugate AZD9592 in patient-derived xenograft (PDX) models of metastatic colorectal cancer (mCRC) in context of irinotecan pretreatment and resistance [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 2957.