NALIRIFOX in the treatment of metastatic pancreatic ductal adenocarcinoma: an exploratory analysis of real-world data

Background: NALIRIFOX, a triplet chemotherapy regimen combining nanoliposomal irinotecan, 5-fluorouracil/leucovorin, and oxaliplatin, demonstrated superior survival outcomes versus gemcitabine plus nab-paclitaxel in the NAPOLI 3 trial for metastatic pancreatic ductal adenocarcinoma (mPDAC). However, its performance in routine clinical practice remains underexplored. Patients and methods: This multicenter retrospective study evaluated the real-world efficacy and safety of NALIRIFOX as first-line treatment in 80 patients with mPDAC. Primary endpoints were time to failure of strategy (TFS) and overall survival (OS). Secondary endpoints included treatment-related toxicity, disease control rate (DCR), and molecular subgroup analyses based on homologous recombination repair mutations (HRRm) and KRAS status. Results: Median TFS and OS were 5.66 and 11.15 months, respectively, with improved outcomes (TFS 6.05 months; OS 12.92 months) in patients meeting strict NAPOLI 3 inclusion criteria. DCR was 57.5%, and grade 3-4 toxicities occurred in 22.5% of patients—lower than reported in randomized trials. HRRm patients (20%) achieved significantly prolonged TFS (7.96 versus 5.23 months, P = 0.049) and OS (16.24 versus 11.11 months, P = 0.043). KRAS G12D/V mutations were associated with worse OS (11.15 months versus not reached, P < 0.05), but not TFS. Conclusions: This first real-world analysis of NALIRIFOX confirms its clinical effectiveness and manageable toxicity in an unselected patient population. The favorable outcomes in HRRm subgroups and the prognostic impact of KRAS variants underscore the need for molecular stratification in guiding first-line therapy for mPDAC.