Evaluating third-line therapies in refractory metastatic colorectal cancer: a systematic review and network meta-analysis.

[BACKGROUND] Patients with refractory metastatic colorectal cancer (mCRC) have poor survival outcomes. Treatment options include trifluridine/tipiracil (FTD-TPI) ± bevacizumab, regorafenib, or fruquintinib, though direct comparisons are lacking. Therefore, we conducted a network meta-analysis (NMA) to evaluate the comparative efficacy and safety of these treatments in refractory mCRC.

[METHODS] We performed a systematic search in electronic databases for randomized phase II/III trials evaluating FTD-TPI ± bevacizumab or ramucirumab (RAM), regorafenib at 80 mg with dose escalation (Rego80+) or 160 mg (Rego160), and fruquintinib in refractory mCRC. Outcomes included overall survival (OS), progression-free survival (PFS) and toxicity. Mixed treatment comparisons were made using an NMA, with P-scores computed for relative treatment rankings.

[RESULTS] Eleven studies at low risk of bias were included. Compared to best supportive care (BSC), FTD-TPI, Rego160, and fruquintinib improved OS and PFS. NMA results indicate that FTD-TPI + bevacizumab had superior OS and PFS compared to FTD-TPI + RAM (HR=0.69, 95 %CI 0.52-0.92; HR=0.57, 95 %CI 0.44-0.76), fruquintinib (HR=0.62, 95 %CI 0.44-0.88; HR=0.68, 95 %CI 0.52-0.88), FTD-TPI (HR=0.60, 95 %CI 0.49-0.74; HR=0.44, 95 %CI 0.37-0.53), and Rego160 (HR=0.57, 95 %CI 0.43-0.77; HR=0.45, 95 %CI 0.34-0.58). In patients with prior anti-VEGF exposure, FTD-TPI + bevacizumab showed OS benefit only versus Rego160 (HR=0.45, 95 %CI 0.21-0.96) and PFS benefit only versus FTD-TPI (HR=0.50, 95 %CI 0.30-0.83).

[CONCLUSION] While FTD-TPI with or without bevacizumab, regorafenib, and fruquintinib are superior to BSC, FTD-TPI + bevacizumab may be preferred for patients with refractory mCRC. However, in patients with prior anti-VEGF exposure, FTD-TPI + bevacizumab, fruquintinib, or Rego80+ are viable options with comparable efficacy.