Phase Ib/II study of fruquintinib plus 5-fluorouracil/leucovorin after progression on fruquintinib monotherapy in metastatic colorectal cancer.

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128 Background: Fruquintinib is a standard third-line treatment in metastatic colorectal cancer (mCRC). However, no standard therapeutic regimen is available for mCRC patients who progressed on third-line therapy. Preclinical experiments supported a rationale for combining antiangiogenic therapy and 5-fluorouracil (5FU) in refractory mCRC with evidence for synergy. This open-label phase Ib/II study was designed to determine the safety and efficacy of fruquintinib plus 5-fluorouracil/leucovorin for mCRC patients who progressed on fruquintinib monotherapy. Methods: The enrolled patients would receive fruquintinib at a fixed dose of 4mg once daily (three weeks on, one week off) and 5FU at two dose levels (1800mg/m 2 and 2400mg/m 2 ) CIV 46 hours on day one and day 15, with leucovorin 400mg/m 2 iv 2 hours before 5FU. Treatments were repeated every 28 days. The primary endpoint was determining the recommended phase II dose (R2PD) of 5FU in phase Ib and the six-month OS rate in phase II. Secondary endpoints for phase II included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety. Planned enrollment was 39 patients. Results: No dose-limiting toxicities occurred in the phase Ib dose-escalation study, and the R2PD of 5FU was 2400mg/m 2 . Between April 2020 and June 2024, 24 patients were enrolled in the phase II stage. The median age was 57.5 years old (from 35 to 68), and 58.33% were female. Left-sided colorectal cancer patients accounted for 75%. Sixteen (66.7%) patients harbored KRAS mutation, and one (4%) had BRAF V600E mutation. Regarding the number of lines of systemic therapy, 83.3% received this study regimen as fourth-line therapy and 16.7% as fifth-line or later therapy. As of June 30, 2024, efficacy was assessed in all 24 patients with a DCR of 62.5% (15 stable disease, nine progression disease). The median follow-up time was 16.5 months (95% CI:12.553-20.447). The primary endpoint six-month OS rate was 91.3%, the median PFS was 4.4 months (95% CI: 1.243-7.557), and the median OS was 17.3 months (95% CI: 12.892-21.708). The most common TRAEs were nausea (25%), hand-foot syndrome (16.7%), abnormal liver function (8.3%), and proteinuria (8.3%). One patient experienced grade 3 mucositis. No treatment-related death occurred. Conclusions: Fruquintinib plus 5-fluorouracil/leucovorin regimen preliminarily demonstrated promising efficacy with a tolerable safety profile for mCRC patients despite progression on prior fruquintinib monotherapy. Further investigation into this possible later-line regimen in mCRC is warranted. Clinical trial information: ChiCTR2000032640 .