Later-line Treatment Selection in Metastatic Colorectal Cancer: Trifluridine/Tipiracil Plus Bevacizumab, Regorafenib, and Fruquintinib.

Later-line therapy for metastatic colorectal cancer (mCRC) increasingly requires selection among treatments with different mechanisms, toxicity profiles, and sequencing evidence. Trifluridine/tipiracil plus bevacizumab has robust randomized evidence from SUNLIGHT, but objective response remains uncommon and hematologic toxicity can limit treatment delivery in heavily pretreated patients. Regorafenib and fruquintinib are minimally myelosuppressive oral alternatives, yet they differ in dose strategy, hepatotoxicity, hand-foot skin reaction, hypertension, and proteinuria. This narrative review updates pivotal and recent evidence and proposes an evidence-informed framework that treats hematologic reserve as a clinical fitness construct rather than a fixed laboratory threshold. We additionally examine the clinical implications of low response rates, prior anti-angiogenic exposure, emerging molecular predictors including KRAS G12, evidence in older or vulnerable patients, and recent phase III developments. Current data do not support a validated molecular biomarker for choosing among these three options, and no randomized head-to-head comparison of regorafenib and fruquintinib exists. Accordingly, treatment selection should be individualized according to prior therapies, toxicity vulnerability, organ function, tumor tempo, and patient goals. Hypertension and proteinuria are important selection factors but may also be modifiable treatment-delivery factors. The proposed algorithms and adverse-event radar chart are intended as practical visual syntheses rather than validated guidelines or formal cross-trial comparisons.