Abstract C140: BI 1810631 is a novel EGFR wild-type sparing, HER2-selective small molecule inhibitor that efficiently blocks HER2 mutant-driven lung cancer

Abstract

Here we report pre-clinical characterization of the clinical compound BI 1810631, a HER2 specific, EGFR wild-type-sparing tyrosine kinase inhibitor (TKI). BI 1810631 has shown early signs of clinical activity in patients carrying tumors with HER2 aberrations [NCT04886804], mainly comprising HER2 mutations (Heymach et al. 2023). In non-small cell lung cancer, activating mutations in HER2 are found in 2-4% of patients and predominantly cluster in exon 20 within the tyrosine kinase domain (TKD), of which the most frequent variant is A775_G776insYVMA. Studies across tumor cell lines and xenograft mouse models show that BI 1810631 is a potent and selective inhibitor of HER2-driven oncogenic signaling. Compound-mediated reduction of cell growth and survival was observed in mutant HER2 driven Ba/F3 cell systems, in human tumor cell lines in vitro and translated into tumor regressions in a genome-engineered HER2-YVMA mutant xenograft model. The in vivo efficacy of BI 1810631 was further confirmed in HER2 exon 20 mutant patient-derived tumor models. Corresponding biomarker studies in vitro and in vivo showed modulation of pharmacodynamic markers, corroborating the on-target mechanism of action of the compound. These findings demonstrate that HER2 mutations can be effectively addressed by BI 1810631 and support the ongoing and future clinical trials.

Citation Format: Ralph A. Neumüller, Birgit Wilding, Dirk Scharn, Anke Baum, Martin Augsten, Irene Waizenegger, Shinji Kohsaka, Valeria Santoro, Paolo Chetta, Lydia Woelflingseder, Johannes Popow, Daniel Gerlach, Peter Ettmayer, Thomas Gerstberger, Julian Fuchs, Matthias Treu, Stephan Zahn, Mark Pearson, Mark Petronczki, Darryl B. McConnell, Norbert Kraut, Flavio Solca. BI 1810631 is a novel EGFR wild-type sparing, HER2-selective small molecule inhibitor that efficiently blocks HER2 mutant-driven lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C140.