Sequential Treatment with Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer

Background: The optimal sequencing of regorafenib and trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal cancer (mCRC) remains uncertain, particularly in Asian populations. Methods: We retrospectively analyzed 110 patients with mCRC who sequentially received both agents between 2011 and 2025. Patients were categorized into regorafenib followed by FTD/TPI (Rego → FTD/TPI, n = 88) and FTD/TPI followed by regorafenib (FTD/TPI → Rego, n = 22). Co-primary endpoints were time to treatment discontinuation (TTD) and overall survival (OS). Propensity score-based weighting methods, including stabilized inverse probability of treatment weighting (primary analysis), were used to adjust for baseline imbalances. Multivariable Cox regression was performed as a sensitivity analysis. Results: No statistically significant differences were observed between treatment sequences. In the primary analysis, the hazard ratio (HR) for TTD was 1.01 (95% CI 0.71–1.43), and for OS was 1.19 (95% CI 0.67–2.12), with FTD/TPI → Rego as reference. Median TTD was 6.8 versus 8.9 months, and median OS was 14.6 versus 20.2 months, respectively. Conclusions: Clinical outcomes were comparable regardless of treatment order, supporting individualized sequencing decisions in refractory mCRC.