Abstract 5350: OBX02-011, a reversible fourth-generation EGFR-TKI, overcomes C797S-mediated resistance in non-small cell lung cancer

Abstract

Abstract Osimertinib, an irreversible, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is initially developed to overcome EGFR T790M mutation, and use as standard therapy in patients with advanced non-small cell lung cancer (NSCLC) including EGFR activating mutations as well as EGFR T790M mutation. Despite remarkable efficacy of osimertinib, this therapy is limited by the emergence of acquired resistance, like other EGFR-TKIs. Since epidermal growth factor receptor mutation C797S was founded as the factor of acquired resistance to osimertinib, drug targeting the clinically relevant C797S mutation has not yet been developed. Here, we reported the discovery and preclinical efficacy of OBX02-011, fourth EGFR-TKI targeting overcome EGFR C797S mutation. Compared with the approved EGFR-TKIs, this agent showed potent anticancer effects and the inhibition of EGFR-related signaling in various models including EGFR C797S mutation. Additionally, we evaluated the efficacy of OBX02-011 in transgenic models (EGFRL858R+T790M+C797S), showing the enhanced survival, and inhibition of tumor growth and EGFR activity. Collectively, our data suggest that OBX02-011 may be promising new EGFR-TKI to overcome C797S-mediated resistance in NSCLC. Citation Format: Da-Som Kim, Yun Jung Choi, Young Hoon Sung, Dong Ha Kim, Chae Won Lee, Kyungtaek Lm, Hyeonjeong Lee, Sung-Eun Kim, Sunho Lee, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho. OBX02-011, a reversible fourth-generation EGFR-TKI, overcomes C797S-mediated resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5350.