HER2 gene mutations and amplifications are common in breast, ovarian, stomach, and lung cancers. Residual EGFR inhibition constrains the therapeutic efficacy of existing pan-ERBB and HER2 inhibitors due to dose-limiting adverse effects. Additionally, intrinsic compensatory pathways in HER2- driven malignancies may substantially increase the required exposure level for sustained pharmacological suppression of HER2 signaling in vivo.
In cancers driven by HER2, feedback loops sustain HER2 hyperactivation, potentially elevating the dose or exposure threshold required for clinical efficacy up to 1000-fold. Therefore, improved selectivity for HER2 over EGFR can mitigate dose-related toxicities linked to EGFR suppression, thereby enhancing the therapeutic window for HER2-targeted agents.
IAM1363 is a covalent HER2 inhibitor binding to the inactive DFG-out conformation of HER2 WT. IAM1363 demonstrated enhanced HER2/EGFR kinetic selectivity vs. reference molecules (Zongertinib and ELVN-002) in COVALfinder® assays, showing over 1000-fold selectivity against EGFR. This led to exceptional in vivo efficacy and tolerability in various HER2-driven cancer models, including those resistant to existing HER2-targeted agents…