The combination of the KRAS G12C inhibitor adagrasib and the anti-EGFR antibody cetuximab showed clinical activity and promising survival outcomes in patients with metastatic, heavily pretreated, KRAS G12C–mutated colorectal cancer, according to findings presented by Kopetz et al at the AACR Annual Meeting 2024 and simultaneously published by Yaeger et al in Cancer Discovery. In the phase I/II KRYSTAL-1 trial, researchers analyzed the safety and efficacy of adagrasib alone or in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS G12C mutations. In the trial, 94 patients with metastatic, KRAS G12C–mutated colorectal cancer received adagrasib plus cetuximab. The objective response rate was 34% and the disease control rate was 85.1%, and responses lasted a median of 5.8 months. The median progression-free survival was 6.9 months, and the median overall survival was 15.9 months. Although the trial was not designed to compare the outcomes of patients treated with adagrasib plus cetuximab with those treated with adagrasib alone, the combination therapy performed favorably compared with historical data. For instance, adagrasib alone was observed to have a response rate around 20% in similar cohorts compared with the higher rate observed in the new trial. The combination therapy is currently under Priority Review by the U.S. Food and Drug Administration and the regimen is also being evaluated in the phase III KRYSTAL-10 trial (ClinicalTrials.gov identifier NCT04793958). “Our study builds upon the progress made with KRAS G12C inhibitors and underscores the importance of ongoing research to refine and expand treatment options for patients with colorectal cancer,” concluded lead study author Scott Kopetz, MD, PhD, Professor of Gastrointestinal Medical Oncology and Associate Vice President of Translational Integration at The University of Texas MD Anderson Cancer Center.