NALIRIFOX plus targeted therapy as first-line treatment for metastatic colorectal cancer: A phase I study.

3564 Background: FOLFOXIRI combined with targeted therapy is recommended for metastatic colorectal cancer (mCRC) patients suitable for intensive treatment or conversion surgery. However, the combination of irinotecan liposome, oxaliplatin, fluorouracil (NALIRIFOX) in mCRC remains uninvestigated. This Phase I study aimed to determine the maximum tolerated dose (MTD) of irinotecan liposome in this combined therapy for mCRC. Methods: Patients with histologically confirmed and initially unresectable mCRC were enrolled. In the dose-escalation phase (Phase Ia), a 3+3 design was utilized. Eligible patients received fixed doses of oxaliplatin (85mg/m 2 ), fluorouracil (2400mg/m 2 ) and bevacizumab (5mg/kg), while the dose of irinotecan liposome was escalated starting from 60mg/m 2 . If a dose-limiting toxicity (DLT) occurs at 60mg/m 2 , the dose can be reduced to 50mg/m 2 . Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE5.0). In the dose-expansion phase (Phase Ib), irinotecan liposome was administered at the recommended dose from Phase Ia. Based on the RAS/BRAF gene status, either bevacizumab or cetuximab was combined with NALIRIFOX. The safety and efficacy of the combination were further assessed in Phase Ib. Results: From March 2024 to March 2025, 9 patients in the dose-escalation phase and 64 patients in the dose-expansion phase were enrolled, included 48 males and 25 females with a median age of 57 years. The MTD of irinotecan liposome was determined to be 50mg/m². Identified DLTs included grade 3 diarrhea and febrile neutropenia. As of January 15, 2026, 65 patients had at least one tumor assessment. The objective response rate (ORR) was 81.5% and the disease control rate (DCR) was 100.0%. The median PFS was 12.3 months (95% CI 9.8-14.7). The rate of R0 resection was 12.3%. The most common ≥grade 3 treatment-related adverse events (TRAEs) were diarrhea (18.4%) and neutropenia (14.5%). Conclusions: Irinotecan liposome at a dose of 50 mg/m² in the NALIRIFOX regimen showed manageable safety and promising efficacy as first-line treatment for mCRC. Clinical trial information: NCT06225622 .