Primary objectives:~To determine the optimal biological dose (OBD) of MRTX849 when used in combination with cetuximab and irinotecan.~To evaluate the safety profile of this combination.~To determine the antitumor activity of this combination in patients with metastatic KRASG12C colorectal cancer.~Exploratory objectives:~To explore correlations between MRTX849 exposure and patient outcomes such as disease response, objective response rate (ORR), duration or response (DOR), progression-free survival (PFS), overall survival (OS), safety, and pharmacodynamic endpoints.~To evaluate the utility of detecting KRASG12C mutation in plasma to identify suitable patients.~To explore potential pharmacodynamic (PD) markers of KRASG12C and EGFR inhibition in tumor tissue and/or blood plasma.~To explore correlations between baseline tumor biomarkers, gene alterations, and clinical activity/efficacy.~To define mechanisms of acquired resistance to EGFR and KRASG12C inhibition and evaluate novel strategies to overcome such resistance.~To assess pharmacokinetics of MRTX849 and irinotecan and key metabolites.
To find the recommended dose of MRTX849 that can be given in combination with cetuximab and irinotecan to patients with colorectal cancer that have a mutation (genetic change) called KRAS G12C.