Abstract LB327: Discovery and characterization of ABSK112, a next-generation and potential best-in-class EGFR Exon20 mutant inhibitor with superior selectivity and brain penetration ability
Authors: Ning Mei , Yang Shuqun , Peng Juan , Hu Shuangyun , Lu Weijia , Dai Cheng , Zhao Baowei , Zhang Mingming , Yu Hongping , Chen Zhui , Xu Yao-chang 
Published: April 2023

Abstract
Introduction: EGFR Exon20 mutations are clinically validated oncogenic alterations including a wide spectrum of mutations occurring in lung cancer and various other cancer types. Although several EGFR Exon20 inhibitors have reached clinical stage or received approval, there still leave large room for improvement in safety and efficacy, likely due to their limited selectivity against wild-type EGFR or other kinases, suboptimal mutation coverage, and lack brain penetrating ability. Herein, we have discovered a novel and next-generation EGFR Exon20 mutation inhibitor, ABSK112. It showed high selectivity over wild-type EGFR and other kinases, as well as a more comprehensive coverage over majority of EGFR Exon20 mutations in comparison with other EGFR Exon20 inhibitors.
Method: Anti-proliferation experiments in cell lines harboring various EGFR Exon20 mutations were used to evaluate potency and spectrum of coverage for ABSK112 and other inhibitors. Efficacy studies and PK/PD study in multiple tumor models confirmed its in vivo activities. Cell proliferation and in vivo efficacies studies in models harboring mutated or wild type EGFR were used to demonstrate its selectivity. Kinome selectivity, safety profiles, PK and ADME profiles were also characterized.
Results: ABSK112 showed potent inhibition of proliferation in multiple EGFR Exon20 mutation cell lines and superior wild-type EGFR selectivity compare to other inhibitors including mobocertinib (TAK788). In xenograft mouse models with various EGFR Exon20 mutations, oral dose of ABSK112 showed strong and dose-dependent anti-tumor efficacy. Moreover, ABSK112 exhibited much reduced in vivo inhibition against xenograft tumors with wild-type EGFR, compared to mobocertinib, confirming its superior selectivity. PK/PD analysis showed good correlation between ABSK112 exposure and inhibition of EGFR signaling. ABSK112 also demonstrated excellent preclinical brain penetration, bioavailability, and safety profile.
Conclusion: ABSK112 is a novel and next-generation EGFR Exon20 mutation inhibitor with improved selectivity over wild-type EGFR and strong brain penetrating ability. It has demonstrated superior in vivo efficacy in several xenograft models with various EGFR Exon20 mutations, and excellent drug-like properties supporting its further development into clinical studies.
Citation Format: Mei Ning, Shuqun Yang, Juan Peng, Shuangyun Hu, Weijia Lu, Cheng Dai, Baowei Zhao, Mingming Zhang, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of ABSK112, a next-generation and potential best-in-class EGFR Exon20 mutant inhibitor with superior selectivity and brain penetration ability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB327.