Metastatic Colorectal Cancer Beyond Third-Line Treatment: Systematic Review and Meta-Analysis of Later-Line Therapies

Objectives: To evaluate and indirectly compare overall survival (OS) and safety of regorafenib, fruquintinib, and trifluridine/tipiracil (TAS-102) monotherapy in refractory metastatic colorectal cancer (mCRC) beyond the third line. Methods: A systematic review and meta-analysis of phase II/III randomized controlled trials was conducted according to PRISMA guidelines. PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched from inception. Eligible studies included patients with mCRC previously treated with standard chemotherapy and biologic agents, receiving regorafenib, fruquintinib, or TAS-102 as monotherapy in the fourth line or later. OS data were reconstructed from published Kaplan-Meier curves. Pooled median and mean OS were estimated using a random-effects model, and heterogeneity was assessed using the I² statistic. Safety outcomes were descriptively summarized. Results: Four RCTs were included. The pooled median OS was 7.83 months (95% CI: 6.98-8.80), and the pooled mean OS was 8.90 months (95% CI: 8.00-9.81), with no heterogeneity (I² = 0%). Survival gains versus placebo ranged from 1.4 to 2.6 months. Survival curves largely overlapped, with differences below one month. Safety was consistent with known profiles. Conclusions: These agents provide comparable efficacy with modest survival benefit in late-line mCRC, highlighting the need for improved strategies and better treatment sequencing.