Treatment Selection Beyond Second Line in Metastatic Colorectal Cancer: Practical Sequencing of Cytotoxic Salvage Therapy, Anti-angiogenic Agents, Rechallenge Strategies, and Biomarker-Guided Treatments.

Treatment selection beyond second line in metastatic colorectal cancer (mCRC) has evolved from empirical salvage therapy to individualized sequencing. Regorafenib, trifluridine/tipiracil (FTD/TPI), FTD/TPI plus bevacizumab, and fruquintinib have established roles in refractory disease, but their optimal order remains patient-dependent. In parallel, biomarker-guided options for BRAF V600E, KRAS G12C, HER2-positive, MSI-H/dMMR, and rare fusion-positive tumors have expanded the treatment framework. After BREAKWATER, BRAF V600E-mutated mCRC should no longer be viewed only as a later-line subgroup, because eligible patients may already have received first-line encorafenib, cetuximab, and fluoropyrimidine-based chemotherapy. Anti-EGFR rechallenge, preferably guided by circulating tumor DNA, provides another biologically dynamic strategy for selected RAS/BRAF wild-type, left-sided tumors. In Japan, OncoGuide EpiLight has introduced clinically implementable DNA methylation testing, which may complement anti-EGFR sensitivity assessment but does not replace resistance-mutation testing. This review summarizes key evidence and proposes a practical scenario-based framework integrating molecular reassessment, comprehensive genomic profiling, residual toxicity, vascular risk, marrow reserve, frailty, patient preference, and trial access.