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

作者：Ying Zheng, Edward Rosfjord, Simon Christ, Stephanie Zalesak‐Kravec, Italia Grenga, Fernanda I. Arnaldez, Frank I. Comer, Lara McGrath · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-2961 · 被引用次数：3 · 研究领域：Medical Imaging Techniques and Applications、Cancer Treatment and Pharmacology、Cancer Cells and Metastasis

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 wildt...