Abstract 1980: Validation of a novel Type II HER2 inhibitor through preclinical studies across various cancer models

Abstract HER2 activation through amplification, overexpression or mutation drives many types of human cancers, and has been the target of several therapeutic approaches. The demonstration of clinical benefit of available pan-ERBB and HER2 inhibitors has been hampered by the dose-limiting side effects from their collateral or residual EGFR inhibition. Here we present IAM1363 (also known as ENT-H1), a highly potent and selective irreversible inhibitor of both HER2 wild-type and HER2 oncogenic mutants. IAM1363 binds to HER2 in a type II DFG-out conformation, the only example reported to date for this target. This binding mechanism underlies its strong interactions with HER2, including N-terminally truncated HER2 (p95HER2) and HER2 kinase domain mutants, with cellular IC50s in the low nanomolar range, while sparing WT EGFR. Oral administration of IAM1363 in mice led to tumor regression (TR) in a diverse set of HER2-driven tumor models at levels well below the maximum tolerated dose (MTD). Importantly, strong in vivo efficacy was observed in tumor models that exhibited resistance to the existing HER2-targeting agents. For example, in a p95HER2 xenograft model, IAM1363 caused significant TR, including complete responses, at 100 mg/kg dose, whereas tucatinib achieved at best tumor stasis at MTD and T-DXd showed marginal effect. Besides HER2 truncation, co-occurring EGFR and other receptor tyrosine kinase (RTK) amplification or overexpression can also lead to resistance to HER2-directed treatments. IAM1363 was tested in xenograft models using HER2-amplified/EGFR-high cell lines HCC1954 and SKOV3, and demonstrated robust TRs. Even more strikingly, IAM1363 led to TR in the HCC827 human lung cancer xenograft model with mid-level HER2, and high levels of EGFR and MET expression. The resistance combatting effect of IAM1363 goes beyond co-occurring RTK-mediated mechanism as IAM1363 also showed dose-dependent TR in KYSE410, a human esophageal squamous cancer xenograft model that harbors the KRAS G12C mutation and HER2 amplification. Taken together, IAM1363 represents a promising clinical candidate for the treatment of HER2-driven tumors. Its unique binding mechanism and potent pan-HER2 activity overcome multiple resistance mechanisms, and its strong EGFR avoidance widens the safety margin. Additionally, IAM1363 was found to be consistently enriched in xenograft tumors that had moderate to high HER2 expression levels, and those with HER2 activating mutations. This distinctive pharmacokinetic property facilitates optimal target engagement in tumors, including those occurring in the brain, while minimizing potential systemic side effects. Citation Format: Lana Kulyk, Kelly Chen, Iriny Botrous, Chunmei Zhao, Chang Zhao, Michael Maestre, Shawn Wright, Joseph Dennis, Jeeyoung Park, Abby Adams, Wallace Derricotte, Shane Yost, Mary L. Anderson, Fred Manby, Tom Miller, Chao Zhang, Laurent Gomez, Zhongdong Huang. Validation of a novel Type II HER2 inhibitor through preclinical studies across various cancer models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1980.