NALIRIFOX in combination with adebrelimab for advanced biliary tract cancer: A phase 2 NIOFA-01 clinical trial.

4120 Background: The NIOFA-01 trial was designed to evaluate the efficacy and safety of liposomal irinotecan combined with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) plus adebrelimab as first-line treatment for patients with advanced biliary tract cancer (BTC) (ChiCTR2400089696). Methods: This single-arm, phase II study enrolled 27 patients with previously untreated, unresectable or metastatic BTC. Patients received NALIRIFOX (liposomal irinotecan 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m² administered as a continuous intravenous infusion over 46 hours), in combination with the PD-L1 inhibitor adebrelimab (1200 mg administered intravenously), every 2 weeks for up to 12 cycles. This was followed by adebrelimab maintenance therapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Additionally, patients were evaluated for tumor gene alterations and PD-L1 expression, and underwent plasma proteomic and serum cytokine profiling. Results: Between September 13, 2024 and January 12, 2026, 27 patients were enrolled, with a median follow-up of 13.8 months (range, 2.8-16.2). Among these patients, the ORR was 55.6% (95%CI, 35.3%-74.5%) and the DCR was 81.5% (95%CI, 61.9%-93.7%). Median PFS was 8.0 months (95% CI, 5.8-9.7), while median OS was not reached (6 months OS rate: 92.6%, 12 months OS rate: 77.8%). Treatment-related adverse events (TRAEs) occurred in 100% of patients, with grade ≥3 TRAEs observed in 55.6%. The most common TRAEs were neutropenia, leukopenia, anemia, and diarrhea. Immune-related adverse events were reported in 74.1% of patients, including hepatotoxicity, hypothyroidism, and cardiac events. Exploratory analyses suggested the ORR was observed to be higher in patients with a CPS score ≥5 compared to those with a score <5 (p = 0.043). Combined analysis of plasma proteomics and metabolomics revealed that in patients who did not respond to treatment, ATP5PD, CTNND2, GALK1, 6nPropyluracil, and 1(Methylsulfinyl) propyl propyl disulfide were significantly elevated, while MMP2 was significantly decreased. A machine learning-based efficacy prediction model was constructed, and ROC curves were generated using the aforementioned four proteins and two metabolites, respectively, with AUC values of 0.961 and 0.883. Additionally, we observed that serum IL2 was significantly elevated in patients who responded to treatment, while IL8 showed a dynamic decreasing trend during the treatment process. Conclusions: NALIRIFOX in combination with adebrelimab demonstrated promising antitumor activity and an acceptable safety profile as first-line treatment for patients with advanced BTC, warranting further validation. Clinical trial information: ChiCTR2400089696.