Biomarker-Guided Treatment Selection in Metastatic Colorectal Cancer: A Critical Review of Established and Emerging Therapies.

Metastatic colorectal cancer (mCRC) is increasingly managed according to mismatch repair status and actionable molecular alterations. In this structured narrative review, we separately examine mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and microsatellite-stable/mismatch repair-proficient (MSS/pMMR) disease and distinguish established treatments from investigational strategies. In dMMR/MSI-H mCRC, immune checkpoint inhibition is the established first-line standard, with pembrolizumab and nivolumab plus ipilimumab producing durable disease control. In MSS/pMMR mCRC, tumor molecular findings guide targeted therapy. For BRAF V600E-mutant disease, encorafenib plus cetuximab with fluoropyrimidine-based chemotherapy is a first-line standard. HER2-directed therapy with tucatinib plus trastuzumab or trastuzumab deruxtecan and combined KRAS G12C and EGFR inhibition are established after prior treatment but are not approved in the first-line setting. Across MMR subgroups, rare NTRK or RET fusions can confer eligibility for tumor-agnostic TRK or RET inhibition, although CRC-specific cohorts remain small. In previously treated non-MSI-H/dMMR mCRC, STELLAR-303 was the first phase 3 trial to demonstrate a significant overall survival benefit with an immune checkpoint inhibitor-containing regimen, zanzalintinib plus atezolizumab. Other investigational strategies include additional immunotherapy combinations, EGFR-MET bispecific antibody therapy with amivantamab, T-cell-engaging bispecific antibodies, therapeutic cancer vaccines, cellular therapies, and microbiome-directed approaches. For each therapeutic class, we summarize the supporting evidence, define its place in the treatment sequence, and identify the remaining evidence gaps.