Abstract 1744: Preclinical efficacy of a selective, orally bioavailable HER2 small molecule inhibitor targeting HER2 alterations and Enhertu-resistant cancers

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Abstract HER2 alterations, including overexpression, amplification, and other mutations are found in various solid tumors and have a significant impact on cancer cell growth and metastasis. To address this issue, HER2-targeted therapeutics are being developed and evaluated across multiple tumor types, including breast cancer, gastric cancer, HER2-positive cholangiocarcinoma, colorectal cancer, non-small cell lung cancer, and bladder cancer. Existing HER2 inhibitors inhibit not only HER2 alteration but also EGFRWT, causing issues with EGFR-related toxicity (skin rash, diarrhea, etc.). This highlights the need to develop selective HER2 inhibitors that specifically target HER2 and its mutations without affecting EGFRWT. The Hanmi compound selectively targets the HER2 receptor tyrosine domain via covalent binding, sparing EGFRWT and minimizing EGFR-related toxicity. The Hanmi compound inhibited both HER2 mutant and HER2WT cells and enzymes, had a DMPK profile compatible with oral administration. It also demonstrated potent antitumor activity as a single agent in various HER2 mutant xenograft models. Despite the good efficacy of Enhertu (trastuzumab deruxtecan), which is approved for the treatment of all HER2 cancers, resistance that develops within 12 months of drug administration remains a major clinical challenge. To address this unmet need, we evaluated a novel HER2 inhibitor in a preclinical model that acquired resistance to Enhertu. The Hanmi compound effectively inhibited tumor growth in Enhertu resistant NCI-N87 mouse models. In conclusion, Hanmi compound, an orally bioavailable small molecule inhibitor, showed high efficacy against both HER2 mutant and HER2WT tumors, while preserving EGFRWT and minimizing EGFR-related toxicities. Furthermore, it demonstrated the potential to overcome resistance to Enhertu by effectively inhibiting tumor growth in Enhertu-induced resistant xenograft mouse model, and these preclinical results support Hanmi compound as a promising treatment for HER2 altered cancers. Citation Format: Jiyoung Jeon, Sun Young Jang, Ho Yeon Nam, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Soye Jeon, Young Gil Ahn. Preclinical efficacy of a selective, orally bioavailable HER2 small molecule inhibitor targeting HER2 alterations and Enhertu-resistant cancers [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 1744.

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