Efficacy and safety of fruquintinib combined with chemotherapy versus bevacizumab combined with chemotherapy as second-line treatment for metastatic colorectal cancer: A prospective, multicenter, randomized controlled trial.

LBA3563 Background: The optimal second-line treatment for metastatic colorectal cancer (mCRC) after failure of oxaliplatin-based chemotherapy therapy remains an area of active research, while bevacizumab combined with chemotherapy is a standard option. Fruquintinib (Fru) is a highly selective and potent oral tyrosine kinase inhibitor of VEGFR 1, 2, and 3. This study aimed to compare the efficacy and safety of fruquintinib combined with chemotherapy versus bevacizumab combined with chemotherapy as second-line treatment for mCRC. Methods: This was a non-inferiority trial conducted across 12 hospitals and cancer centers in China. Patients with mCRC who had progressed on fluoropyrimidine and oxaliplatin-based first-line chemotherapy therapy were randomly assigned (1:1) to receive either Fru (4 mg orally, once daily for 3 weeks on/1 week off) plus FOLFIRI, or bevacizumab (Bev) (5 mg/kg intravenous, every 2 weeks) plus FOLFIRI. Randomization was stratified by primary tumor location and RAS/BRAF status. During combination therapy, pts who achieve disease control after 4-6 months of treatment proceeded to maintenance therapy, receiving either fruquintinib combined with capecitabine or bevacizumab combined with capecitabine. The primary endpoint was progression-free survival (PFS). Final analysis occurred after either 97 PFS events or after the last patient had completed 12 months of follow-up, whichever occurred first. The non-inferiority upper margin of HR was 1.33. Results: Between Jul 13, 2023, and Mar 4, 2025, 122 pts were enrolled and randomly assigned to the Fru group (n=60) or the Bev group (n=62). The median age was 59.0 (IQR 54-69) and 60.0 (IQR 51-70) years, 45 (75%) and 48 (77%) had left-sided tumors, 36 (60%) and 36 (58%) were RAS/BRAF mutant, respectively. At data cut-off (Feb 28, 2026), the median PFS of the Fru group was non-inferior to the Bev group, whether in the Intention to Treat Population (ITT) (9.40 vs 7.39 months, hazard ratio HR=0.806 95% CI 0.522–1.244, 80% CI 0.607-1.07; p=0.33) or the per-protocol set (PPS) (9.49 vs 7.85 months, HR=0.848 95% CI 0.542–1.326, 80% CI 0.633-1.136; p=0.469). In the subgroup analysis , the Fru group showed longer PFS in prior never used VEGF inhibitor pts (10.6 vs 8.5 months, HR=0.94, 95% CI 0.54-1.62), and pts without liver metastasis (14.5 vs 9.9 months, HR=0.97, 95% CI 0.43-2.22) compared to the Bev group. The objective response rate was 35.0% with Fru vs 22.6% with Bev group. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% (Grade ≥3, 28.1%) of the Fru group and 93.2% (Grade ≥3, 28.8%) of the Bev group. Conclusions: Fruquintinib combined with FOLFIRI demonstrated non-inferiority in PFS compared with bevacizumab combined with FOLFIRI as a second-line treatment for mCRC, with a manageable safety profile. Clinical trial information: NCT05555901 .