Fruquintinib versus trifluridine-tipiracil plus bevacizumab versus regorafenib in refractory metastatic colorectal cancer: A propensity score–matched real-world analysis.

134 Background: Fruquintinib, trifluridine-tipiracil plus bevacizumab (FTD/TPI+bev), and regorafenib are approved for refractory metastatic colorectal cancer (mCRC), yet no head-to-head trials compare all three. Real-world data directly comparing these regimens—particularly since all three became simultaneously available after fruquintinib's FDA approval (November 2023)—are lacking. Methods: Using the TriNetX Global Collaborative Network (170 healthcare organizations), adults with mCRC (ICD-10 C18–C20 plus C78–C79) initiating fruquintinib, FTD/TPI+bev (bevacizumab within 30 days of FTD/TPI), or regorafenib were identified. Three pairwise 1:1 propensity score–matched (PSM) analyses adjusted for demographics, Charlson comorbidities, metastatic burden, and baseline labs (albumin, creatinine, hemoglobin, platelets, ALP, LDH, CEA). The primary outcome was overall survival (OS; Kaplan-Meier with log-rank test). Secondary outcomes included adverse events and healthcare utilization (ED visits, hospitalizations). Results: Before PSM, 648 fruquintinib, 2,302 FTD/TPI+bev, and 5,944 regorafenib patients were identified. After matching, all covariates were well balanced (SMD <0.1). FTD/TPI+bev demonstrated significantly longer OS than both fruquintinib (median 11.7 vs 9.9 mo; HR 1.36, 95% CI 1.09–1.68, P=0.005; n=431 pairs) and regorafenib (median 11.8 vs 9.2 mo; HR 1.26, 95% CI 1.13–1.40, P<0.001; n=1,247 pairs). Fruquintinib and regorafenib showed comparable OS (median 8.9 vs 8.6 mo; HR 0.98, 95% CI 0.80–1.20, P=0.81; n=413 pairs). FTD/TPI+bev had significantly higher neutropenia (15.6% vs 5.3%, P<0.001) and thrombocytopenia (9.6% vs 5.7%, P=0.001) versus regorafenib. Hypertension trended higher with fruquintinib versus regorafenib (14.8% vs 9.3%, P=0.12); hand-foot syndrome trended higher with regorafenib versus fruquintinib (6.6% vs 3.8%, P=0.10). No significant differences in hepatotoxicity, diarrhea, GI bleeding, ED visits, or hospitalizations were observed across comparisons. Conclusions: In this real-world analysis, FTD/TPI+bev was associated with significantly superior OS versus both fruquintinib and regorafenib in refractory mCRC, with a 2–3 month median survival advantage. This benefit was accompanied by higher myelosuppression. Fruquintinib and regorafenib showed comparable efficacy with distinct toxicity profiles. These findings support FTD/TPI+bev as a preferred option and highlight the need for individualized treatment selection balancing efficacy and tolerability.