Biomarker-guided treatment selection in metastatic colorectal cancer: A critical review of established and emerging therapies.
Tojjari Alireza A, Pourbahrighesmat Shamimeh S, Alkhazna Shahd S, Saeed Anwaar A
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.