The Anti-Tumor Activity Of The Kras G12c Inhibitor Mrtx849 Is Augmented By Cetuximab In Crc Tumor Models

The ability to develop effective therapies for KRAS mutant cancers has remained elusive despite decades of research. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor presently under evaluation in clinical trials. MRTX849 inhibits only inactive GDP-bound KRASG12C, a mutation known to be dependent on nucleotide cycling and extrinsic factors which regulate the activation state of KRAS. Preclinical and early clinical data suggest KRASG12C inhibitors induce tumor regression/response in a subset of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models and patients. Previous work in tumor xenograft models demonstrated activation of pathways upstream or downstream of KRAS through additional mutations or relief of feedback inhibition can limit the single agent activity of MRTX849 in the less responsive tumors. These data indicated that activation of receptor tyrosine kinases (RTKs) through relief of feedback inhibition was one mechanism implicated in modulating the response to MRTX849. As KRAS G12C mutations are present in ~4% of colon cancer, MRTX849 was further evaluated in CRC models to identify combination strategies that might optimize anti-tumor activity. A range of responses to single agent MRTX849 were observed across cell line and patient-derived xenograft (PDX) models. The combination of MRTX849 plus cetuximab demonstrated the best anti-tumor activity in multiple models. The combination of MRTX849 and cetuximab demonstrated increased KRASG12C modification and MAPK pathway inhibition suggesting these therapies converge to more fully inhibit KRASG12C. Despite the fact that cetuximab-based therapy is contra-indicated for KRAS-mutant CRC, these data suggest co-targeting EGFR and KRAS may more comprehensively inhibit KRAS mediated signaling and more effectively treat a subset of CRC patients with KRASG12C-mutant cancers. Citation Format: Jill Hallin, Andrew Calinisan, Lauren Hargis, Ruth Aranda, Lars D. Engstrom, David M. Briere, Matthew A. Marx, Peter Olson, James G. Christensen. The anti-tumor activity of the KRAS G12C inhibitor MRTX849 is augmented by cetuximab in CRC tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-098.