OBJECTIVE: This study aims to evaluate the real-world effectiveness and safety of sequential treatment with regorafenib and trifluridine/tipiracil (FTD-TPI) in patients with metastatic colorectal cancer (mCRC) in Taiwan. METHODS: Data were obtained from Taiwan's National Health Insurance Research Database (NHIRD) to assess clinical outcomes in mCRC patients who were treated with both drugs in either sequential order from 2016 to 2019. Overall survival (OS) was analyzed using Kaplan-Meier curves and Cox's proportional hazard models, with adjustments made for age, gender, Quan-CCI score, presence of liver metastases, number of metastatic sites, and the use of anti-epidermal growth factor receptor medications. Additionally, age-stratified subgroups and sensitivity analyses were conducted to examine the robustness of our findings. RESULTS: Five hundred and twenty-eight patients receiving both study drugs were included. The regorafenib/FTD-TPI group demonstrated a longer median OS of 14.1 months compared with 10.2 months in the FTD-TPI/regorafenib group (p = 0.007). The survival benefit for the regorafenib/FTD-TPI sequence remained significant after adjustment (adjusted HR, 1.49
p = 0.002). The mean treatment duration was also longer for regorafenib/FTD-TPI than FTD-TPI/regorafenib (337 vs. 214 days
p <
0.01). No significant difference between the sequential treatment groups was observed in any adverse event of interest. Both subgroup and sensitivity analyses yielded outcomes consistent with the main analysis. CONCLUSION: The findings indicated that initiating treatment with regorafenib followed by FTD-TPI had superior clinical outcomes compared with the reverse sequence among mCRC patients. This study offers real-world evidence for clinical decision-making and treatment optimization.