e15571 Background: Despite advances in therapeutic strategies, patients (pts) with metastatic colorectal cancer (mCRC) have limited options for third- or later-line (≥ 3L) therapies. Previous studies have demonstrated that fruquintinib combined with chemotherapy exhibits favorable anti-tumor activity. Liposomal irinotecan (naI-IRI), a modified formulation of irinotecan, has undefined safety and efficacy profile in mCRC pts with prior irinotecan exposure. This study aimed to investigate the maximum tolerated dose (MTD) and preliminary efficacy of naI-IRI combined with fruquintinib in the ≥ 3L treatment of mCRC pts who have failed prior irinotecan-based therapy. Methods: Unresectable advanced colorectal cancer patients who have failed ≥ 2L of standard chemotherapy and prior irinotecan-based regimens were enrolled. This phase I study adopted a 3+3 dose-escalation design plus expansion cohorts at the recommended dose. Eligible pts received naI-IRI at one of three predefined dose levels (50, 60 and 70 mg/m 2 ) on day 1 and 15, in combination with a fixed oral dose of fruquintinib (4mg/d) administered using a 3-week on/1-week off schedule every 4 weeks. The primary endpoint was MTD determination. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and dose-limiting toxicities (DLT). Results: As of Oct 2025, 12 pts were enrolled. The median age was 63 years range: 50-74, 75.0% were male, and 83.3% had an ECOG performance status of 1. 8 pts (66.7%) had ≥2 metastatic sites; the predominant metastatic locations were the lungs (66.7%), liver (50.0%), lymph nodes (41.7%) and peritoneum (25.0%). During dose escalation, no DLT was detected in the naI-IRI 50 mg/m 2 dose cohort. Two DLTs (grade 3 diarrhea and grade 3 febrile neutropenia) occurred in the 60 mg/m² cohort. Therefore, the MTD was determined to be 50 mg/m 2 . Subsequently, 6 pts were enrolled in the dose expansion cohort. Among the 50 mg/m² naI-IRI cohort (n = 9), ORR was 33.3% and DCR was 77.8%. mPFS was 6.30 months (95% CI, 4.90-not reached NR). Treatment-emergent adverse events (TEAEs) occurred in all 12 (100%) pts. Among them, 6 pts (50.0%) experienced grade 3 AEs, including diarrhea (25.0%), febrile neutropenia (8.3%), neutropenia (8.3%), anemia (8.3%), and hand-foot syndrome (8.3%); all these events resolved following symptomatic treatment. No grade 4-5 events occurred. Conclusions: The MTD of naI-IRI (on day 1 and 15) combined with fruquintinib (3-week on / 1-week off) every 4 weeks was 50 mg/m 2 . Furthermore, this phase I study demonstrated that the combination regimen exhibited an acceptable safety profile and promising efficacy in pts with mCRC who progressed on ≥ 2L of standard therapies and failed irinotecan-based treatment. Collectively, these findings warrant further investigation of this regimen in mCRC pts. Clinical trial information: ChiCTR2400092084.
Li et al. (Thu,) studied this question.