Abstract LB_C14: EAI-432: A mutant-selective allosteric EGFR inhibitor for L858R-mutant non-small cell lung cancer

Abstract

Abstract While osimertinib is highly efficacious in lung cancers with sensitizing mutations in EGFR, there is a major unmet need for agents that overcome resistance to it and other covalent third-generation EGFR TKIs due to the C797S mutation. Furthermore, osimertinib extends overall survival in patients with exon19 deletions but offers little improvement in overall survival in patients with the L858R mutation relative to the first-generation inhibitors. We are developing EAI-432 with the goal of improving outcomes for patients with EGFRL858R+ lung cancer. EAI-432 is a mutant-selective allosteric inhibitor that is effective against L858R and its common resistance variants, L858R/T790M, L858R/C797S, and L858R/T790M/C797S while sparing WT EGFR. The compound induces tumor regressions in a L858R/T790M/C797S mouse xenograft model at low doses (5 mg/kg). In the H1975 (L858R/T790M) xenograft model, EAI-432 induced marked tumor regressions in both subcutaneous and intracranial implants. EAI-432 co-binds with osimertinib, allowing double-drugging of the mutant receptor. The distinct binding site and allosteric mechanism of EAI-432 are expected to confer exquisite kinome-wide selectivity and orthogonal resistance mechanisms as compared with osimertinib and other ATP-competitive TKIs, properties that are highly desirable in a combination agent. The compound has efficacy, mutant-selectivity, and pharmacokinetic properties including brain-penetrance that support its further development as a therapeutic agent for EGFRL858R+ lung cancer alone or in combination with osimertinib. Citation Format: Michael J. Eck, David A. Scott, Pasi Janne, Tyler S. Beyett, Jie Jiang, Praful Gokhale, Thomas W. Gero. EAI-432: A mutant-selective allosteric EGFR inhibitor for L858R-mutant non-small cell 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 LB_C14.