Abstract 5437: Preclinical characterization of EB160, a novel, highly potent and brain-penetrant KRASG12C inhibitor
Authors: Chen Xuxing , Li Jing , Chen Yanhong 
Published: June 2022

Abstract
The KRASG12C mutation is present in nearly 13% of lung adenocarcinoma, 3% of colorectal cancer and 2% of other solid tumors. AMG510 developed by Amgen and MRTX849 developed by Mirati Therapeutics both target the KRASG12C mutation through covalent modification of the Cys 12 of the mutated protein. According to the disclosed clinical data, AMG510 and MRTX849 have an ORR of 36-45% in NSCLC and of 7-22% in CRC patients harboring a KRASG12C mutation. Incomplete target occupancy is considered to be a potential reason for only less than 50% of patients with KRASG12C mutation benefiting from those KRASG12C inhibitors. Brain metastases developed from lung cancer, accounting for 40-50% of all brain metastases, were described as the primary or contributing cause of death in a large proportion of patients with brain metastases from NSCLC. About 55% of NSCLC patients with KRAS mutations develop brain metastases. The KRAS mutant patients with untreated brain metastasis from NSCLC have a median OS of only 5 months. Hence, in order to achieve maximal clinical benefit in patients with KRASG12C mutation, a highly potent, brain-penetrant KRASG12C inhibitor with sufficient continuous exposure for the complete dose interval to maximize depth and duration of antitumor activity is required. Here, we report the discovery of EB160, a novel, highly potent and brain-penetrant KRASG12C covalent inhibitor. In a panel of KRASG12C mutant cancer cell lines, EB160 inhibited the proliferation of these cells with higher potency compared to AMG510 and MRTX849. EB160 also inhibited phosphor-ERK in H358 cells with an IC50 value of 17.54 nM at 1 h, while the IC50 values of AMG510 and MRTX849 were 58.98 nM and 41.89 nM, respectively. In vitro ADME, EB160 showed moderate or high stability in liver microsomes across the species tested, and the whole blood t1/2 was greater than 240 min in mouse, rat, dog and human, which was comparable to MRTX849. Following single PO dose (5 mg/kg) in mice, rats and dogs, the mean AUC(0-∞) were 2679 ng*h/mL, 2855 ng*h/mL and 1511 ng*h/mL, respectively, and the absolute bioavailabilities were 86%, 78% and 32%, respectively. A H358 cell line-derived lung cancer xenograft model was selected for in vivo efficacy assay. At 10 mg/kg QD of EB160 for 28 days, the tumor growth inhibition (TGI) was 108.2%, with 5 out of 6 mice showing tumor regression &gt; 80% from initial baseline. And in the 30 mg/kg treatment group, whole 6 mice showed near complete tumor regression. In the H1373Luc KRASG12C brain metastases model, 30 mg/kg QD EB160 oral dose in mice for 28 days results in tumor regression 92%, while in the same dosage of MRTX849 treatment group, the tumor regression was 50%.
Citation Format: Xuxing Chen, Jing Li, Yanhong Chen. Preclinical characterization of EB160, a novel, highly potent and brain-penetrant KRASG12C inhibitor [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 5437.