Abstract LB525: Discovery and characterization of ABSK111, a selective, CNS-penetrable, and broad-spectrum EGFR inhibitor targeting exon20 insertion, atypical and extracellular mutations

Abstract

Abstract Epidermal growth factor receptor (EGFR) exon20 insertion mutations and atypical mutations account for about 9% and 20% of EGFR-mutated non-small cell lung cancer (NSCLC), respectively. Currently approved EGFR tyrosine kinase inhibitors (TKIs) have shown efficacy in NSCLC patients with exon20 insertion and atypical mutations, but with limited overall response and high rate of EGFR-related severe adverse events. This may be associated with the inhibition of wild-type (WT) EGFR. ABSK111 is a highly potent, selective, and CNS-penetrable EGFR inhibitor, targeting multiple EGFR and HER2 mutations, including exon20 insertion, atypical, and extracellular mutations. Here we describe the preclinical in vitro and in vivo characterization of ABSK111. ABSK111 potently inhibited the proliferation of BA/F3 cell lines harboring EGFR exon20, atypical and extracellular mutations with higher selectivity for WT EGFR than currently approved EGFR TKIs. ABSK111 also suppressed HER2 atypical and exon20 mutations. Further, ABSK111 potently blocked the phosphorylation of EGFR exon20 insertion mutations and EGFR variant III in BA/F3 cell lines, with less inhibition of WT EGFR signal than the approved TKIs. Moreover, pharmacokinetic and pharmacodynamic studies demonstrated sustained and exposure-dependent suppression of p-ERK in tumor tissue following a single oral dose of ABSK111. Finally, ABSK111 showed dose-dependent anti-tumor activity in BA/F3 tumor models with EGFR exon20 insertion mutations and EGFR variant III without significant body weight loss. Pharmacodynamic analysis of endpoint samples from efficacy study showed sustained inhibition of p-ERK, which was superior to the approved exon20 insertion inhibitor mobocertinib. Taken together, these results demonstrate the ability of ABSK111 to inhibit a broad spectrum of EGFR and HER2 mutations, including exon20 insertions, atypical and extracellular mutations, while sparing the WT form of EGFR. In addition to the application in NSCLC, the activity against EGFR extracellular mutations and the ability to penetrate into brain suggest the application of ABSK111 in glioblastoma multiforme (GBM). Citation Format: Cheng Dai, Juan Peng, Fei Yang, Haibing Deng, Yuan Zhao, Hongping Yu, Yaochang Xu, Zhui Chen, Shuqun Yang. Discovery and characterization of ABSK111, a selective, CNS-penetrable, and broad-spectrum EGFR inhibitor targeting exon20 insertion, atypical and extracellular mutations [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 LB525.