Multikinase inhibitors in refractory metastatic colorectal cancer: an optimal sequence?

Despite major advances in management strategies, metastatic colorectal cancer remains an important clinical challenge because most patients experience progression after standard first- and secondline treatments. In the setting of refractory disease, defined as disease that progresses after 2 or more lines of treatment, the therapeutic landscape is growing. Options include regorafenib, trifluridine plus tipiracil (FTD/TPI) with or without bevacizumab, and fruquintinib, all of which received approval from the US Food and Drug Administration after showing modest survival benefits in phase 3 trials. However, optimal sequencing remains undefined owing to the absence of direct comparative studies. Real-world data suggest that sequencing regorafenib before FTD/TPI may improve outcomes, with the addition of bevacizumab to FTD/TPI offering further survival benefit. Fruquintinib has also shown efficacy after the use of regorafenib and/or FTD/TPI. Therefore, treatment decisions are based on a case-by-case scenario, with factors such as comorbidities, preferred route of administration, and tolerability taken into consideration. Additionally, improved patient stratification with biomarker testing has become essential for guiding personalized treatment selection. This review highlights the current evidence and gaps in sequencing strategies for the treatment of refractory metastatic colorectal cancer, highlighting the need for future research to inform personalized, effective, and sustainable treatment pathways.