Abstract 5477: Compound A, a fourth-generation allosteric inhibitor, a potent and highly selective EGFR with L858R activating and C797S resistance mutations for the treatment of NSCLC
Authors: Byeon Yeji , Jung Seung Hee , Yoon Daseul , Kang Seock Yong , Park Jiyeon , Jo Hyeim , Choi Seong-Il , Park Somyi , Lee Seung-chul , Tae Yang Hun , Kim Tae Min , Cho Sung-Yup , Kim Soyeon , Ko Donghyun , Kim Dong-Kyu , Kim Dong-Wan 
Published: June 2022

Abstract
The L858R activating mutation in Epidermal Growth Factor Receptor (EGFR) accounts for approximately 40% of EGFR-mutant non-small cell lung cancer (NSCLC). These patients receive targeted therapy targeting EGFR mutation. To date all approved EGFR tyrosine kinase inhibitors (TKIs) are ATP competitive inhibitors, inevitably lead to drug resistance and to disease progress. Osimertinib is a third-generation EGFR TKI that selectively inhibits both EGFR TKI-sensitizing (L858R) mutation and T790M mutation that confers acquired resistance to first- and second-generation EGFR-TKIs. The patients develop secondary resistance L858R/C797S and L858R/T790M/C797S to this treatment in some cases. There have been strong unmet needs for specific therapies targeting C797S resistance mutations. Additionally, toxicities caused by inhibition of wild-type (WT) EGFR are frequently reported with the first-generation inhibitors (e.g. Gefitinib and Erlotinib). Our Compound A is a highly mutant-selective fourth-generation allosteric inhibitor that targets L858 activating mutations and without affecting EGFR WT that compares favorably with all ATP competitive inhibitors, indicating that it might avoid potential toxicities from targeting EGFR WT. Compound A has a single-digit nanomolar potency against L858R activating mutation and those harboring T790M and C797S resistance mutations. Oral administration of Compound A to tumor-bearing mice showed significant antitumor activity as a single-agent at well-tolerated doses via inhibiting EGFR pathway in the engineered osimertinib-resistance EGFRL858R/T790M/C797S and EGFRL858R/C797S CDX models. Furthermore, Compound A demonstrated excellent efficacy in EGFRL858R/T790M CDX model as a single-agent. Collectively, Compound A has a robust potency against L858R activating mutations including T790M, C797S, and T790M/C797S that cause acquired resistance to ATP competitive EGFR TKIs in vitro and in vivo. Based on the preclinical data, Compound A is a potent, orally available, and mutant-selective fourth-generation allosteric inhibitor of EGFR with L858R activating mutations for the treatment of NSCLC, suggesting that it might have the potential to demonstrate activity in the first line and resistance settings as a single agent. The pre-clinical data described here supports the clinical development of Compound A in NSCLC patients with L858R activating mutations of EGFR.
Citation Format: Yeji Byeon, Seung Hee Jung, Daseul Yoon, Seock Yong Kang, Jiyeon Park, Hyeim Jo, Seong-Il Choi, Somyi Park, Seung-chul Lee, Yang Hun Tae, Tae Min Kim, Sung-Yup Cho, Soyeon Kim, Donghyun Ko, Dong-Kyu Kim, Dong-Wan Kim. Compound A, a fourth-generation allosteric inhibitor, a potent and highly selective EGFR with L858R activating and C797S resistance mutations for the treatment of NSCLC [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 5477.