In previously treated patients with mCRC, drugs such as fruquintinib, regorafenib, and TAS-102 may be associated with different clinical outcomes due to their different molecular mechanisms. Fruquintinib is a potent, highly selective small-molecule inhibitor of vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3, and is an anti-angiogenic compound. However, regorafenib is a targeted pan-kinase inhibitor for the VEGFR family, and for fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), KIT, RET, and BRAF. Regorafenib was designed as salvage therapy in previously treated malignances, including hepatocellular carcinoma (HCC) [12], advanced gastrointestinal stromal tumors (GISTs) [13], and advanced gastric cancer [14]. TAS-102 is an orally administered combination of a thymidine-based nucleic acid analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride and is a chemotherapy agent. Although the mechanism of the anti-tumor effects in the three agents, fruquintinib, regorafenib, and TAS-102 is different, positive outcome data in patients with refractory mCRC was previously demonstrated in RCTs and provided the evidence to support their recommended use in current clinical guidelines [4,7].