Abstract 3090:<i>In vivo</i>characterization of AMG 510 - a potent and selective KRAS^G12Ccovalent small molecule inhibitor in preclinical KRAS^G12Ccancer models

Somatic activating mutations of RAS family members are tumor driver mutations found in an estimated 21% of all cancers. Oncogenic KRAS mutations at residues G12, G13, and Q61 represent the most common RAS mutations found in solid malignancies. The prevalence of KRAS p.G12C tumors is ~13% of lung adenocarcinoma (including NSCLC), 3% of colorectal carcinoma (CRC), and 1% to 2% of numerous other solid tumors, representing an unmet medical need. We have developed AMG 510, an orally bioavailable, covalent inhibitor of KRASG12C with potent biochemical and cellular activity, and robust in vivo efficacy. AMG 510 inhibited SOS-catalyzed nucleotide exchange of recombinant mutant KRASG12C/C118A but had minimal effect on KRASC118A, which is wildtype at position 12. In cellular assays, AMG 510 covalently modified KRASG12C and inhibited KRASG12C signaling as measured by phosphorylation of ERK1/2 (p-ERK) in all KRAS p.G12C-mutant cell lines tested but did not inhibit p-ERK in cell lines with various other KRAS mutations. AMG 510 also selectively impaired viability of KRAS p.G12C mutant cell lines but did not affect cell lines with other KRAS mutations. In vivo pharmacodynamic assays demonstrated dose- and time-dependent inhibition of KRASG12Csignaling in human pancreatic and NSCLC tumor xenografts. Covalent modification of KRASG12C by AMG 510 was measured by mass spectrometry and correlated with p-ERK inhibition in tumors. AMG 510 significantly inhibited the growth of KRAS p.G12C xenografts and resulted in tumor regression. Combination treatment of AMG 510 with standard-of-care and targeted agents demonstrated enhanced tumor growth inhibition compared to either single agent. In a syngeneic model of KRAS p.G12C mutant cancer, AMG 510 treatment significantly inhibited tumor growth and caused regression. AMG 510 is currently in Phase 1, first-in-human clinical trials for patients with advanced solid tumors harboring a KRAS p.G12C mutation.Citation Format: Karen Rex, Anne Y. Saiki, Ji-Rong Sun, Tyler Holt, Neelima Koppada, Brian A. Lanman, Laurie P. Volak, Robert S. Foti, Victor J. Cee, J. Russell Lipford, Jude Canon. In vivo characterization of AMG 510 - a potent and selective KRASG12Ccovalent small molecule inhibitor in preclinical KRASG12Ccancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3090.