Background
Phase III open-label RCT (NAPOLI-3), N=770 patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) with ECOG PS 0–1. Stratified by geographic region, ECOG PS, and presence of liver metastases. Enrolled 2019–2021 across 187 sites globally.
Interventions and follow up
Arm A: NALIRIFOX — liposomal irinotecan 50 mg/m² + oxaliplatin 60 mg/m² + leucovorin 400 mg/m² + 5-FU 2400 mg/m² CI q2wk
Arm B: Nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² days 1, 8, 15 q4wk
Primary endpoint: Overall survival (OS)
Median follow-up: 16.1 months
Arm B: Nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² days 1, 8, 15 q4wk
Primary endpoint: Overall survival (OS)
Median follow-up: 16.1 months
Results
OS: 11.1 vs 9.2 months, HR 0.83 (95% CI 0.70–0.99), P=.036
PFS: 7.4 vs 5.6 months, HR 0.69 (95% CI 0.58–0.83), P<.001
ORR: 42.3% vs 36.2%, P=.08
PFS: 7.4 vs 5.6 months, HR 0.69 (95% CI 0.58–0.83), P<.001
ORR: 42.3% vs 36.2%, P=.08
Adverse events
Hematologic: Grade ≥3 neutropenia 15% vs 24%, hypokalemia 15% vs 5%.
Gastrointestinal: Grade ≥3 diarrhea 20% vs 5%, nausea 11% vs 6%.
Non-hematologic: Grade ≥3 fatigue 10% vs 10%, peripheral neuropathy 3% vs 6%.
Overall: Grade ≥3 AEs 68% vs 62%; treatment discontinuation 14% vs 13%.
Gastrointestinal: Grade ≥3 diarrhea 20% vs 5%, nausea 11% vs 6%.
Non-hematologic: Grade ≥3 fatigue 10% vs 10%, peripheral neuropathy 3% vs 6%.
Overall: Grade ≥3 AEs 68% vs 62%; treatment discontinuation 14% vs 13%.
Conclusions
NALIRIFOX significantly improved OS and PFS compared to nab-paclitaxel+gemcitabine in previously untreated metastatic PDAC (OS 11.1 vs 9.2 months, HR 0.83, P=.036), establishing NALIRIFOX as a new first-line option. The PFS improvement was more pronounced (HR 0.69), and ORR was numerically higher with NALIRIFOX.
Key Limitations
Modest absolute OS benefit (1.9 months median). The reference arm (nab-paclitaxel+gemcitabine) was chosen based on MPACT data but FOLFIRINOX is also a standard first-line regimen — NALIRIFOX was not directly compared to FOLFIRINOX, limiting full context of benefit. NALIRIFOX has a more complex administration schedule (q2wk vs q4wk) and distinct toxicity profile (more diarrhea, hypokalemia vs nab-paclitaxel's neuropathy), requiring careful patient selection. No biomarker-selected subgroups (BRCA1/2, KRAS G12C) were pre-specified as the primary analysis. KRAS inhibitors (sotorasib, adagrasib, MRTX-849) are entering first-line PDAC trials and may reshape the landscape. Data on quality of life not mature at primary analysis.
Clinical Context
FDA approved liposomal irinotecan (Onivyde) combined with oxaliplatin and 5-FU/leucovorin (NALIRIFOX) in February 2024 for first-line metastatic PDAC, based on NAPOLI-3 — the first new first-line approval for PDAC since nab-paclitaxel+gemcitabine in 2013. Three first-line standards now exist for fit patients with metastatic PDAC: FOLFIRINOX, nab-paclitaxel+gemcitabine, and NALIRIFOX. NALIRIFOX was directly compared only to nab-P+gem; its relative benefit vs FOLFIRINOX remains undefined. Germline BRCA1/2 status should be assessed in all patients (POLO trial) as olaparib maintenance is approved after platinum-based first-line. ESMO-MCBS: not yet scored at time of entry.
References