Comparing the Effectiveness and Safety of Different Third-Line Management Options for Patients with Metastatic Colorectal Cancer: A Systematic Review and Reconstructed Individual Patient Data Meta-Analysis.

Metastatic colorectal cancer (mCRC) that progresses after standard first- and second-line therapies carries a poor prognosis, and multiple third-line treatment options are available without a clearly established optimal strategy.

This study aimed to comprehensively compare the efficacy and safety of currently approved third-line treatments using reconstructed individual patient data (reconstructed IPD). A systematic review and reconstructed IPD meta-analysis of phase III randomized controlled trials was conducted in accordance with PRISMA-IPD guidelines. Kaplan-Meier survival curves were digitized and reconstructed using validated methodologies. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS) and the incidence of grade ≥3 treatment-related adverse events (AEs).

A total of 3338 patients were included across five treatment groups: regorafenib (n = 650), fruquintinib (n = 739), trifluridine/tipiracil (TAS-102; n = 780), TAS-102 plus bevacizumab (n = 246), and pooled placebo (n = 923). TAS-102 plus bevacizumab demonstrated the greatest benefit (OS HR: 0.43, 95% CI: 0.35-0.50; median OS: 10.89 months; PFS HR: 0.20, median PFS: 5.51 months). Fruquintinib (OS HR: 0.67; median OS: 7.97 months; PFS HR: 0.32; median PFS: 3.70 months) and TAS-102 (OS HR: 0.70; median OS: 7.2 months; PFS HR: 0.41; median PFS: 2.09 months) showed comparable survival benefit to regorafenib (OS HR: 0.68; median OS: 7.04 months; PFS HR: 0.39; median PFS: 2.16 months), with fruquintinib demonstrating superior PFS versus regorafenib (HR: 0.71, p < 0.001). Grade ≥3 AEs were highest with TAS-102 plus bevacizumab (72.36%) and lowest with fruquintinib (34.02%), with hematologic toxicity predominating in TAS-102-based regimens and hypertension and hand-foot skin reactions more common with tyrosine kinase inhibitors.

TAS-102 plus bevacizumab was associated with the greatest survival benefit in this indirect comparison and appears to be the most effective option for eligible patients.

However, these findings should be interpreted cautiously given the absence of direct head-to-head trials. Among tyrosine kinase inhibitors, fruquintinib demonstrated superior PFS compared with regorafenib, while OS was comparable.