Abstract 1057: Combination of the KRASG12C inhibitor sotorasib with targeted agents improves anti-tumor efficacy in <i>KRAS p.G12C</i> cancer models

Abstract KRAS is the most frequently mutated oncogene in cancer and encodes a key signaling protein in tumors. The p.G12C mutation of KRAS is present in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer, and 2% of other solid tumors. Sotorasib (formerly known as AMG 510), the first KRASG12C inhibitor to reach clinical testing in humans, has demonstrated evidence of clinical activity as a single agent in patients with non-small cell lung (NSCLC), colorectal (CRC), endometrial, and appendiceal carcinoma. Preclinically, sotorasib has shown significant tumor growth inhibition as a single agent in multiple CDX and PDX models. The clinically-validated strategy of combining multiple inhibitors in the MAPK pathway suggests that combination strategies could yield even better outcomes for patients. Specifically, the combination of sotorasib and other inhibitors in the MAPK and AKT signaling pathways might further enhance tumor cell killing and overcome potential resistance. To test this hypothesis, in vitro combination experiments were conducted in multiple KRAS p.G12C cell lines with combination matrices of sotorasib and inhibitors of HER kinases, EGFR, SOS1, SHP2, MEK, PI3K, or mTOR, as well as an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). The combination of sotorasib with multiple agents resulted in robust synergistic cell killing of KRAS p.G12C tumor cells in vitro. To understand whether these observations translated in vivo, we assessed combinations of sotorasib with a SHP-2 inhibitor or a HER kinase inhibitor in pharmacodynamic assays and efficacy models in tumor xenografts. Consistent with the synergy observed in vitro, sotorasib in combination with a HER kinase inhibitor (afatinib) or a SHP2 inhibitor (RMC-4550) in vivo resulted in enhanced inhibition of MAPK signaling as measured by p-ERK in NCI-H358 tumors. In efficacy studies using the NCI-H358 xenograft model, significantly enhanced anti-tumor activity was observed with a minimally efficacious dose of sotorasib in combination with afatinib, RMC-4550, or a CDK4/6 inhibitor (palbociclib). Furthermore, enhanced anti-tumor activity was observed with sotorasib in combination with a MEK inhibitor or with the anti-EGFR monoclonal antibody panitumumab in a CRC KRAS p.G12C PDX model. Taken together, these data support the clinical evaluation of combination treatment of sotorasib with analogous agents in patients with KRAS p.G12C tumors. Citation Format: Karen Rex, Anne Y. Saiki, Tyler Holt, Alla Verlinsky, Patricia L. McElroy, Tao Osgood, Ji-Rong Sun, Marwan G. Fakih, Upendra P. Dahal, Bernd Bruenner, Victor J. Cee, Brian A. Lanman, Jude Canon, J. Russell Lipford. Combination of the KRASG12C inhibitor sotorasib with targeted agents improves anti-tumor efficacy in KRAS p.G12C cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1057.