Abstract 1229: BDTX-1535: A MasterKey EGFR inhibitor targeting classical and non-classical oncogenic driver mutations and the C797S acquired resistance mutation to address the evolving molecular landscape of EGFR mutant NSCLC

Abstract The molecular landscape of EGFR mutated NSCLC has evolved over time in response to changing treatment practices with EGFR inhibitors and through the expanding use of NGS. With the replacement of first-generation reversible EGFR tyrosine kinase inhibitors (TKIs) by the third generation covalent TKI osimertinib as front-line therapy for patients with NSCLC expressing classical EGFR mutations, acquired resistance mutations have shifted with the near disappearance of EGFR-T790M and the emergence and growing incidence of EGFR-C797S. Our understanding of the EGFR mutation landscape has also continued to mature with comprehensive sequencing across all EGFR exons and with the vast majority of patients now undergoing sequencing. We now see how classical oncogenic drivers represent only a subset of oncogenic EGFR driver mutations and where other non-classical driver mutations are numerous and represent a major unmet medical need. Furthermore, there is a growing appreciation of the differences between the classical EGFR-L858R and EGFR-Ex19 deletion (Ex19del) mutations. For patients expressing L858R, many co-express non-classical drivers and this may explain the weaker relative activity for osimertinib in patients expressing L858R versus Ex19del. For patients expressing Ex19del, the co-expression of non-classical mutations is less common. In contrast, patients with Ex19del more often gain C797S as an acquired resistance mutation. Using the Foundation Medicine’s FoundationInsights™ web-based platform, we present real world evidence (RWE) to define the molecular landscape of classical, non-classical, and acquired resistance mutations from a survey of >80,000 sequenced cases of NSCLC, including >12000 EGFR altered cases. We further present the profile for BDTX-1535 as a MasterKey EGFR inhibitor designed to address this evolved EGFR mutational landscape and tested against over >50 EGFR mutations. We also show how BDTX-1535 can address classical EGFR mutations in addition to on target mechanisms of resistance post osimertinib with potency against C797S as well as non-classical mutations affecting both the intracellular and extracellular domains, including L718X, E709X, S784F, V834L and A289V. Citation Format: Etienne Dardenne, Matthew O'Connor, Monique Nilsson, Junqin He, Xiaoxing Yu, John V. Heymach, Xiuning Le, Elizabeth Buck. BDTX-1535: A MasterKey EGFR inhibitor targeting classical and non-classical oncogenic driver mutations and the C797S acquired resistance mutation to address the evolving molecular landscape of EGFR mutant NSCLC [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(6_Suppl):Abstract nr 1229.