Efficacy and safety of third-line treatments in metastatic colorectal cancer: A meta-analysis.

Abstract

e15623 Background: Metastatic colorectal cancer (mCRC) in the third-line setting has limited options after progression on standard therapies. This systematic review and meta-analysis compares efficacy and safety of trifluridine-tipiracil monotherapy, trifluridine-tipiracil plus bevacizumab, regorafenib, and fruquintinib versus placebo in refractory mCRC. Methods: We conducted a PRISMA-compliant systematic review of phase II/III and phase III randomized trials evaluating third-line treatments for mCRC. Databases included PubMed, Embase, Scopus, and others (up to 2025). Individual patient data (IPD) were reconstructed from digitized Kaplan-Meier curves for pooled estimates of overall survival (OS; primary), progression-free survival (PFS), and grade ≥3 adverse events (AEs). Random-effects models generated hazard ratios (HRs), median survivals (with 95% CIs), and heterogeneity (I²). Results: Data from 3,338 patients across key trials were included: trifluridine-tipiracil (n = 780), trifluridine-tipiracil plus bevacizumab (n = 246), regorafenib (n = 650), fruquintinib (n = 739), placebo (n = 923). Pooled median PFS (95% CI) were: trifluridine-tipiracil 2.09 months (2.00-2.27); trifluridine-tipiracil plus bevacizumab 5.51 months (4.48-5.89); regorafenib 2.11 months (1.92-2.88); fruquintinib 3.71 months (3.67-3.78); placebo 1.83 months (1.78-1.85). Versus placebo, all active arms significantly improved PFS (HRs 0.19-0.43, p < 0.001). Combined TKI arm (regorafenib/fruquintinib) had median PFS 3.53 months (3.35-3.67; HR 0.34, 95% CI 0.30-0.37, p < 0.001). Fruquintinib demonstrated superior PFS versus regorafenib (HR 0.72, 95% CI 0.63-0.82). Pooled median OS (95% CI) were: trifluridine-tipiracil 7.20 months (6.74-7.86); trifluridine-tipiracil plus bevacizumab 10.89 months (9.77-12.06); regorafenib 6.99 months (6.08-8.29); fruquintinib 7.96 months (7.40-8.77); placebo 5.58 months (5.10-6.04). Versus placebo, all active arms significantly improved OS (HRs 0.42-0.72, p < 0.001). Trifluridine-tipiracil plus bevacizumab showed the greatest benefits. Combined TKI arm had median OS 7.66 months (7.22-8.27; HR 0.67, 95% CI 0.60-0.74, p < 0.001). Grade ≥3 AEs included neutropenia/anemia (prominent with trifluridine-tipiracil plus bevacizumab), hypertension (fruquintinib), and hand-foot syndrome (regorafenib). Conclusions: All third-line regimens significantly improve PFS and OS over placebo in refractory mCRC. Trifluridine-tipiracil plus bevacizumab provides the most substantial survival benefit, followed by fruquintinib and regorafenib, with distinct toxicity profiles. These findings, derived from IPD-reconstructed meta-analysis, support trifluridine-tipiracil plus bevacizumab as a preferred option in suitable patients, while highlighting the need for direct head-to-head trials and biomarker-guided selection.