Abstract C069: The identification of MRTX849, a novel KRASG12C inhibitor under clinical investigation, provides insight toward therapeutic susceptibility of KRAS mutant cancers
Authors: Christensen James G , Fell Jay B , Hallin Jill , Baer Brian , engstrom Lars , Blake James , Briere David , Ballard Josh , Burkhard Michael , Fischer John , Vigers Guy , Aranda Ruth , Bowcut Vickie , Calinisan Andrew , Hargis Lauren , Sudhakar Niranjan , Marx Matt , Olson Peter 
Published: March 2020

The ability to effectively target mutated KRAS has remained elusive despite decades of research. MRTX849 was identified via structure-based drug design as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties. MRTX849 is presently under evaluation in clinical trials and its discovery and evaluation is disclosed here for the first time. MRTX849 demonstrated selective modification of the mutant cysteine residue at amino acid residue 12 in GDP-bound KRASG12C and inhibited KRAS-dependent signaling in vitro and in vivo. In multiple KRASG12C positive cell lines in vitro, MRTX849 treatment demonstrated covalent modification of mutant KRAS and/or inhibition of active KRAS at concentrations as low as 2 nM with near maximal inhibition observed at 15 nM. In vivo, clear evidence of dose-dependent modification of KRASG12C and inhibition of KRAS-dependent signal transduction was observed in multiple KRASG12C mutant tumor models. MRTX849 demonstrated marked tumor regression in 17 out of 26 (65%) of KRASG12C-positive cell line- and patient-derived xenograft (PDX) models but not in tumor models without KRASG12C mutations. While MRTX849 commonly elicited tumor regression, a subset of models was less sensitive to treatment or exhibited tumor stasis after an initial response phase. Comprehensive pharmacodynamic and pharmacogenomic profiling in these models identified mechanisms implicated in limiting anti-tumor response in refractory models including extrinsic factors impacting KRAS nucleotide cycling and/or signaling pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included upstream activation of ERBB family receptor tyrosine kinases (RTKs) as well as genetic dysregulation of cell cycle transition genes. Based on these observations, combination strategies designed to co-target signaling feedback and bypass pathways were evaluated in multiple tumor models. Afatinib and the SHP2 inhibitor, RMC-4550, in combination with MRTX849 validated these therapeutic hypotheses and the combinations demonstrated marked tumor regression in several tumor models, including models that were refractory to either single agent. MRTX849 in combination with the CDK4/6 inhibitor palbociclib also demonstrated a marked antitumor response; notably in tumor models harboring CDKN2A deletion or other genetic alterations implicated in cell cycle dysregulation. Together, these data indicate the therapeutic susceptibility and broad dependence of KRAS G12C mutation-positive tumors on KRAS for tumor cell growth and survival and provide insight toward the molecular basis of response to single agent and combinatorial therapies.

Citation Format: James G Christensen, Jay B Fell, Jill Hallin, Brian Baer, Lars engstrom, James Blake, David Briere, Josh Ballard, Michael Burkhard, John Fischer, Guy Vigers, Ruth Aranda, Vickie Bowcut, Andrew Calinisan, Lauren Hargis, Niranjan Sudhakar, Matt Marx, Peter Olson. The identification of MRTX849, a novel KRASG12C inhibitor under clinical investigation, provides insight toward therapeutic susceptibility of KRAS mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C069. doi:10.1158/1535-7163.TARG-19-C069