Abstract LB316: A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models

Abstract

Abstract Background: KRAS is frequently mutated in human cancers, including pancreatic (~90%), colorectal (~35%), and lung cancer (~25%). The KRASG12C mutation (single amino acid substitution of cysteine for glycine at position 12) accounts for ~14% of lung cancer, ~4% of colorectal cancer, and ~2% of pancreatic cancer. Currently, two covalent KRASG12C inhibitors, namely sotorasib (AMG-510) and adagrasib (MRTX-849), have been approved as monotherapy to treat locally advanced or metastatic NSCLC with KRASG12C mutation through accelerated approval process. Despite the beneficial effects of KRASG12C inhibitors in clinic for certain patients, the limited antitumor efficacy in most patients and potential drug resistance are major concerns. A next-generation inhibitor with better inhibitory activity may improve anti-tumor efficacy. Combination with other therapeutic agents may also improve the single-agent activity of KRASG12C inhibitors. These approaches could both overcome the limitations of sotorasib and adagrasib and provide additional benefits to patients. Materials and methods: KRASG12C inhibitory activity of ABSK071 was examined in vitro and in vivo in comparison with sotorasib and adagrasib. To identify potential targeted agents synergizing with ABSK071, we tested a set of inhibitors that targeting signaling components of KRAS pathways, including EGFRi, FGFRi, SHP2i and SOS1i, in combination with ABSK071 in cellular experiments using KRASG12C mutant cell lines. Cell growth inhibition was measured and synergistic effect was analyzed. In vivo efficacy study was also conducted to confirm the synergistic anti-tumor effect in animal models. A set of immuno-oncology reagents, including anti-PD-1/L1, CSF-1R inhibitor (ABSK021) and CD73 inhibitor (ABSK051) were also tested in combination with ABSK071 in vivo using mouse syngeneic models. Results: ABSK071 demonstrated much stronger inhibitory activity than sotorasib and adagrasib against a variety of cell lines harboring KRASG12C, as well as significantly better in vivo anti-tumor efficacy in xenograft models that were less sensitive to sotorasib. Synergistic effects on cell growth inhibition were observed in vitro with ABSK071 in combination with several agents including cetuximab, afatinib, AZD4547, TNO-155, RMC-4630 and BI3406. Superior anti-tumor activities were observed in vivo when these agents were combined with ABSK071 than in combination with sotorasib. In mouse syngeneic models harboring KrasG12C mutations, ABSK071 also demonstrated synergy with anti PD-1/L1 antibody or other IO reagents. Conclusions: ABSK071 is a next-generation KRASG12C inhibitor with greater activity and anti-tumor efficacy in vitro and in vivo. It also demonstrated broad synergistic effects with a large set of targeted agents and immuno-oncology agents, indicating its strong potential in combinatory therapy in treating a wider range of KRASG12C-dependent cancers. Citation Format: Haiyan Ying, Fushen Guo, Juan Peng, Jie Wang, Jie Zhang, Manqi Liu, Zhixuan Zhu, Zhui Chen. A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models [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 LB316.