Pancreas
Lancet. 2023;402(10409):1272–81
NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): A randomized, open-label, phase 3 trial
Background: Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC).
Methods: NAPOLI 3 was a randomized, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomization was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary end point was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the 2 treatment groups. Safety was evaluated in all patients who received at least 1 dose of study treatment.
Findings: Between February 19, 2020 and August 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel-gemcitabine, 387; median follow-up 16.1 months [interquartile range, 13.4–19.1]). Median overall survival was 11.1 months (95% confidence interval [CI]: 10.0–12.1) with NALIRIFOX versus 9.2 months (95% CI: 8.3–10.6) with nab-paclitaxel-gemcitabine (hazard ratio = 0.83; 95% CI: 0.70–0.99; p = 0.036). Grade 3 or higher treatment-emergent adverse events occurred in 322 of 370 patients (87%) receiving NALIRIFOX and 326 of 379 patients (86%) receiving nab-paclitaxel-gemcitabine; treatment-related deaths occurred in 6 patients (2%) in the NALIRIFOX group and 8 patients (2%) in the nab-paclitaxel-gemcitabine group.
Interpretation: These findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of metastatic pancreatic ductal adenocarcinoma.