Abstract 1967: IN-119873, the next-generation allosteric EGFR TKI, a potent and highly selective EGFR L858R for the treatment of osimertinib-resistant NSCLC

Abstract EGFR mutations occur in approximately 50% of Asian patients and 20% of Caucasian patients with non-small cell lung cancer (NSCLC). The EGFR L858R mutation constitutes approximately half of the EGFR-mutated patients, and despite receiving first-line or second-line treatment with the 3rd generation EGFR TKI osimertinib, they continue to exhibit a poor prognosis. According to real-world analysis, the leading resistance mechanism to osimertinib is identified as EGFR C797S mutation. Furthermore, osimertinib is still associated with gastrointestinal and skin toxicity, despite its improved selectivity for EGFR WT compared to 1st-generation EGFR TKIs. Here, we show that IN-119873 can overcome C797S-mediated acquired resistance based on the results obtained by various in vitro and in vivo NSCLC models. IN-119873 binds to an EGFR allosteric site separate from the ATP-binding site with a remarkable preference for highly mutant-selective inhibition. It effectively targets EGFR L858R activating mutations while sparing the inhibition of EGFR WT, which sets it apart from ATP competitive inhibitors. Moreover, oral administration of IN-119873 showed excellent anti-tumor efficacy in a dose-dependent manner in a diverse of osimertinib-resistant CDX and PDX models. IN-119873 also demonstrated favorable blood-brain-barrier penetration with promising intracranial efficacy in the H1975-luc brain metastasis model both mono or in combination with osimertinib. As a selective, orally available, and CNS-penetrable next-generation allosteric EGFR-TKI, IN-119873 is currently undergoing IND-enabling studies and has the potential to demonstrate activity in both first-line and resistance settings, either as a monotherapy or in combination with 3rd generation EGFR TKI. Citation Format: Jong Ryoul Choi, Daseul Yoon, Seo Hyun Kim, Do Gyeong Kim, Seock Yong Kang, Seong-Il Choi, Somyi Park, Hyun Kyung Lee, Donghyun Kim, Ju Hyun Lee, Hye-Jung Kim, Bong Tae Kim. IN-119873, the next-generation allosteric EGFR TKI, a potent and highly selective EGFR L858R for the treatment of osimertinib-resistant 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 (6Suppl): Abstract nr 1967.