Initial dose of fruquintinib and clinical outcomes in patients with refractory metastatic colorectal cancer: a multicenter real-world study

Fruquintinib is an established treatment for patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. However, treatment-related adverse events such as hypertension, hand-foot syndrome, and proteinuria frequently require dose modification or treatment discontinuation in clinical practice. Although dose-optimization strategies have been investigated for regorafenib, real-world evidence regarding initial dose strategies for fruquintinib remains limited. We evaluated the association between initial fruquintinib dose and outcomes in patients with refractory mCRC. This multicenter retrospective study included patients with mCRC who received fruquintinib as third-line or later therapy. Patients were categorized according to the initial fruquintinib dose into a standard-dose group (5 mg) and a reduced-dose group ( < 5 mg). Progression-free survival (PFS), overall survival (OS), dose modification, proteinuria, and early treatment exposure were evaluated. Multivariable Cox proportional hazards models and propensity score-adjusted Cox analyses were performed to address potential selection bias. A total of 69 patients were included (5 mg group, n = 44; <5 mg group, n = 25). Patients in the reduced-dose group generally had worse performance status than those in the 5 mg group. The median PFS in the 5 mg and reduced-dose groups was 3.98 and 3.68 months, respectively (hazard ratio [HR], 1.26; 95% CI, 0.59-2.64; p = 0.54), and the median OS was 7.43 and 5.88 months, respectively (HR, 1.40; 95% CI, 0.60-3.14; p = 0.42). Initial dose was not significantly associated with PFS or OS in multivariable or propensity score-adjusted analyses. Dose reduction was more frequent in the 5 mg group than in the reduced-dose group (45.5% vs 20.0%, p = 0.0406). The median worst post-treatment urine protein-to-creatinine ratio was also significantly higher in the 5 mg group (0.91 vs 0.27, p = 0.0374). The median relative dose intensity during the first 8 weeks of treatment was 66.67% in the 5 mg group and 53.81% in the reduced-dose group ( p = 0.0246). Reduced starting doses of fruquintinib were not associated with inferior survival outcomes in this retrospective cohort. Because of the modest sample size and potential residual confounding, these findings should be considered hypothesis-generating. Individualized initial dose selection based on patient condition and anticipated tolerability may be feasible for selected patients with refractory mCRC.