Abstract 2935: Development of selective HER2 covalent inhibitors with brain penetration for effective treatment of CNS metastases

Abstract HER2 alterations, including amplification, overexpression, and mutations, are implicated in the development and progression of brain metastases (BM) and leptomeningeal metastases (LM) across various cancer types. In breast cancer, BM occurs in 15-25% of patients, with up to 50% of HER2-positive cases developing BM, underscoring the importance of HER2 amplification in metastatic progression. Similarly, HER2 alterations are positively associated with a higher risk of LM, affecting up to 25% of HER2-positive metastatic breast cancer patients. Although HER2 alterations are less common in lung cancer and melanoma, the high incidence of BM (20-40% in lung cancer and up to 50% in melanoma) and LM (3-5% in lung cancer and up to 23% in melanoma) highlights the importance of targeting HER2-driven pathways to manage these aggressive metastatic complications. The role of HER2 mutation and amplification in promoting metastatic progression establishes its significance as both a biomarker and target for tailored therapies. BM and LM are associated with poor prognosis and significantly reduced overall survival. Therefore, effective management of BM and LM requires addressing HER2-driven mechanisms, highlighting the unmet need for selective HER2 inhibitors with brain-penetrating properties capable of targeting both HER2 mutants and HER2WT amplification in HER2-altered BM and LM. Herein, we report the development of potent and selective covalent HER2 inhibitors, the Hanmi compounds, which exhibit strong anti-tumor activity in BM and LM models with high selectivity over EGFRWT. The growth-inhibitory effects of these compounds were evaluated in vitro using cell lines harboring HER2G776insVG/C mutations and HER2WT amplifications. Additionally, their anti-tumor efficacy was assessed in BM and LM mouse models. Hanmi compounds significantly reduced tumor burden and markedly improved survival in mice intracranially implanted with HER2WT-amplified N87 cells. Moreover, in the H1781 LM model harboring HER2G776insVG/C mutations, these compounds demonstrated superior efficacy by significantly increasing median overall survival (mOS) and inhibiting tumor growth compared to the approved HER2 targeting agent. These findings highlight the potential of Hanmi compounds as effective treatments for central nervous system (CNS) metastases, including BM and LM, addressing a critical unmet need in the management of HER2-altered metastatic diseases. Citation Format: Hyunjin Park, Yu-Yon Kim, Jiyoung Jeon, Sun Young Jang, Young Gil Ahn, Haemin Chon. Development of selective HER2 covalent inhibitors with brain penetration for effective treatment of CNS metastases [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 2935.