Phase Ib/II trial of hepatic arterial infusion chemotherapy in combination with fruquintinib for refractory unresectable colorectal cancer liver metastases.

3561 Background: Hepatic arterial infusion chemotherapy (HAIC), a highly efficient local therapy for patients with colorectal liver metastases (CRLM), is supposed to have a synergetic effect when it is in combination with a systemic therapy. The aim of this study was to determine the recommended phase 2 dose (PR2D) of fruquintinib combine with HAIC and evaluate efficacy and safety in expansion cohort of patients with CRLM. Methods: This open-label, single-arm, phase Ib/II study (NCT05406206) enrolled patients with CRLM who had received at least two prior lines of treatment. In the dose-finding phase, based on a standard 3+3 design, patients were treated with HAIC involving oxaliplatin (85 mg/m 2 ) and 5-FU (2000 mg/m 2 ) on day 1 and 2 every 4 weeks, alongside fruquintinib (3mg, 4mg, 5mg, d3-23, q4w, respectively) until unacceptable toxicities, progressive disease, or death occurred. In the dose-expansion phase, patients received HAIC and RP2D of fruquintinib determined in the dose-escalation phase. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included RP2D, objective response rate (ORR; RECIST 1.1), disease control rate (DCR), overall survival (OS) and safety. Results: As of data cutoff date on January 30, 2024, a total of 30 patients were enrolled. 9 (30.0%) patients were female, and the mean age was 56 years, 22 (73.3%) patients were RAS/BRAF mutant. During the dose-escalation phase, 15 patients were enrolled, with 3, 6, and 6 patients receiving doses of 3 mg, 4 mg, and 5 mg, respectively. Only one dose-limiting toxicity occurred in a patient of 4 mg level (G3 hypertension failed to control with antihypertensive treatment within 7 days). RP2D of fruquintinib was established as 5 mg. Fifteen patients were evaluable for efficacy, with best response of pathological complete response in 1 patient, partial response in 5 patients and stable disease in 6 patients, yielding an ORR of 40.0% and DCR of 80.0%. Median hepatic-PFS and median PFS was 6.8 months (95% CI, 5.890-7.710) and 5.9 months (95% CI, 3.576-8.224), respectively. The median OS reached 15.0 months (95% CI, 8.671-21.329). 7 (23.3%) patients experienced G3/4 treatment-related adverse events (TRAEs). The most common TRAEs of all grades were voice alteration, hypertension, abdominal pain and hand-foot syndrome. Conclusions: The combination of HAIC and fruquintinib showed a manageable safety profile and survival benefit of heavily treated CRLM patient. Clinical trial information: NCT05406206 .