Clinical trialPhase 3Pancreatic cancer

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

Lancet · 2023770 patients (383 NALIRIFOX, 387 nab-paclitaxel–gemcitabine)

Wainberg ZA, Melisi D, Macarulla T, et al. Lancet. 2023. 402:1272-1281

Study type: Clinical trial
Study name: NAPOLI 3
Phase: Phase 3
Design: Randomised, open-label trial at 187 centres in 18 countries; 1:1 randomisation stratified by geographic region, performance status and liver metastases
Sample size: 770 patients (383 NALIRIFOX, 387 nab-paclitaxel–gemcitabine)
Source: Lancet · 2023
Trial registration: NCT04083235

In plain words

NALIRIFOX is a regimen similar to FOLFIRINOX in which, instead of ordinary irinotecan, a liposomal form (packaged in tiny fat particles) is used. In this study, patients with pancreatic cancer that had spread who received this regimen lived about 11 months on average, compared with about 9 months with the nab-paclitaxel and gemcitabine regimen. Severe side effects were common in both groups, but of different kinds: diarrhoea was more common with NALIRIFOX and a drop in white blood cells was more common with the comparison regimen.

Key results

11.1 vs 9.2 months

Median overall survival

HR 0.83 (95% CI 0.70–0.99); p=0.036; median follow-up 16.1 months

7.4 vs 5.6 months

Median progression-free survival

HR 0.69 (95% CI 0.58–0.83); P<0.0001 — from the paper, as cited in the ESMO Express Update 2025

42% vs 36%

Objective response

160 vs 140 patients; P=0.11 — from the paper, as cited in the ESMO Express Update 2025

87% vs 86%

Treatment-emergent grade 3 or higher adverse events

322 of 370 vs 326 of 379; treatment-related deaths 6 (2%) vs 8 (2%)

Drugs in this study:Fluorouracil (5-FU)Gemcitabine (Gemzar)Irinotecan (Camptosar)Oxaliplatin (Eloxatin)Paclitaxel (Taxol)

Dose and schedule cards

NALIRIFOX (NAPOLI-3)

First-line metastatic disease; ECOG 0–1; bilirubin within the normal rangeCycle length: Every 28 daysOn the page “Pancreatic cancer” · Metastatic disease: first-line, maintenance and later lines

First-line metastatic disease; ECOG 0–1; bilirubin within the normal range

Drug	Dose	Route	Schedule
Liposomal irinotecan	50 mg/m²	IV over 90 minutes	Days 1 and 15
Oxaliplatin	60 mg/m²	IV over 120 minutes	Days 1 and 15
Leucovorin	400 mg/m²	IV over 30 minutes	Days 1 and 15
Fluorouracil	2400 mg/m²	IV, 46-hour continuous infusion	Days 1 and 15

Cycle length: Every 28 days
Duration: Until disease progression or unacceptable toxicity

Doses and order of administration from the liposomal irinotecan FDA label and NAPOLI-3.

On the page “Pancreatic cancer” · Metastatic disease: first-line, maintenance and later lines

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1NALIRIFOX

On days 1 and 15 of each 28-day cycle, in order: liposomal irinotecan 50 mg/m² IV over 90 minutes, oxaliplatin 60 mg/m² IV over 120 minutes, leucovorin 400 mg/m² IV over 30 minutes and fluorouracil 2400 mg/m² as a continuous IV infusion over 46 hours; until disease progression or unacceptable toxicity.

2Nab-paclitaxel + gemcitabine (control group)

Nab-paclitaxel 125 mg/m² IV over 35 minutes, then gemcitabine 1000 mg/m² IV over 30 minutes, on days 1, 8 and 15 of each 28-day cycle.

Source of the regimen details: Abstract and full text of the paper (PMC11664154) and the FDA label for liposomal irinotecan (ONIVYDE; Clinical Studies section on NAPOLI 3: infusion durations)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults (18 years or older) with pancreatic ductal adenocarcinoma (mPDAC) not previously treated for metastatic disease.
ECOG performance status 0 or 1; at least one measurable metastatic tumour on CT or MRI (RECIST 1.1).
Prior adjuvant chemotherapy was an exclusion criterion unless the last dose was more than 12 months before enrolment with no persistent treatment-related toxicity (full text).

Endpoints

Primary outcome: overall survival in the intention-to-treat population (analysis after at least 543 events).

Secondary outcomes: progression-free survival, overall response rate and safety (in all patients who received at least one dose of treatment).

Safety and side effects

Treatment-emergent grade 3 or higher adverse events occurred in 322 of 370 patients in the NALIRIFOX group (87%) and 326 of 379 patients in the nab-paclitaxel–gemcitabine group (86%). Treatment-related deaths were reported in 6 patients (2%) in the NALIRIFOX group and 8 patients (2%) in the comparator group. Based on the paper's data as cited in the ESMO Express Update 2025, the most common grade 3–4 adverse events with NALIRIFOX versus nab-paclitaxel–gemcitabine were neutropenia (14% versus 25%) and diarrhoea (20% versus 5%).

Clinical significance and place in guidelines

Based on NAPOLI 3, the FDA approved liposomal irinotecan (Onivyde) in 2024 as part of the NALIRIFOX regimen for first-line treatment of metastatic pancreatic adenocarcinoma. The ESMO Express Update 2025 recommends NALIRIFOX alongside FOLFIRINOX for patients with ECOG 0 to 1, bilirubin below 1.5 times the upper limit of normal and no major comorbidity, at level [I, A] (ESMO-MCBS score 2). NCCN (version 4.2026) also lists NALIRIFOX as category 1 for metastatic disease, but stresses that it has no clear superiority over FOLFIRINOX or mFOLFIRINOX; the two regimens have never been compared directly.

Limitations

The study was open-label and the comparator was nab-paclitaxel–gemcitabine, not FOLFIRINOX; superiority of NALIRIFOX over FOLFIRINOX has therefore not been shown. The absolute survival benefit was about 1.9 months, and per ESMO-MCBS a more than 20% increase in grade 3–4 toxicities affecting daily life was reported. Liposomal irinotecan is expensive.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.