KRAS G12C-mutated Metastatic Colorectal Cancer: Current Therapeutic Strategies and Future Directions.

KRAS G12C mutations define a small but clinically important molecular subset of metastatic colorectal cancer (mCRC), accounting for approximately 3% to 4% of cases and remaining associated with substantial unmet need after standard chemotherapy. Although direct KRAS G12C inhibitors have transformed treatment in other tumor types, their activity as monotherapy in mCRC has been modest, largely because colorectal cancer retains strong upstream EGFR and receptor tyrosine kinase dependency with adaptive MAPK pathway reactivation. These observations provide the biologic rationale for combined KRAS G12C and EGFR inhibition. Clinical results are line- and regimen-dependent: sotorasib plus panitumumab improved progression-free survival compared with standard later-line therapy in the randomized phase 3 CodeBreaK 300 trial, whereas adagrasib plus cetuximab demonstrated clinically meaningful activity in KRYSTAL-1 but did not improve progression-free or overall survival versus chemotherapy in the second-line phase 3 KRYSTAL-10 trial despite a higher objective response rate. Available evidence should therefore be interpreted with appropriate caution. Moreover, acquired resistance remains common and frequently polyclonal, involving secondary KRAS alterations, receptor tyrosine kinase bypass, and downstream pathway reactivation. In this review, we summarize the biologic rationale, current clinical evidence, practical guideline-based positioning, toxicity management considerations, resistance mechanisms, and emerging therapeutic strategies for KRAS G12C-mutated mCRC.