# NAPOLI 3

Source: https://onco.cc/trials/napoli-3/  
OnCo record `napoli-3` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The first head-to-head trial of the two chemotherapy backbones, won narrowly by the four-drug regimen.

## Summary

NAPOLI 3, trial NCT04083235 sponsored by Ipsen and reported in 2023, was the first head-to-head trial of the two chemotherapy backbones for first-line metastatic pancreatic cancer, comparing NALIRIFOX, the four-drug regimen built on liposomal irinotecan, with gemcitabine plus nab-paclitaxel. It randomised 770 patients and met its primary overall survival endpoint, with a narrow but statistically significant advantage and a clearer gain in progression-free survival, leading to FDA approval of NALIRIFOX in February 2024. OnCo links it to pancreatic ductal adenocarcinoma, to NALIRIFOX and gemcitabine plus nab-paclitaxel, to Zev A. Wainberg, and to the bottleneck of cold tumours; the result is consistent in direction with PRODIGE 4 for FOLFIRINOX. Critics note the absence of a modified FOLFIRINOX arm, so whether the new regimen beats the older four-drug standard is the open question.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-09-06
- Registry id: NCT04083235
- Phase: 3
- Setting: First-line metastatic PDAC: NALIRIFOX vs gemcitabine + nab-paclitaxel
- Sponsor: Ipsen
- Enrolled: 770
- Result: OS HR 0.84; PFS HR 0.69.
- Outcomes: Overall survival: NALIRIFOX 11.1 months vs Gemcitabine + nab-paclitaxel 9.2 months, HR 0.83
- Replication: Consistent in direction with PRODIGE 4/ACCORD 11 (FOLFIRINOX vs gemcitabine); no direct FOLFIRINOX comparison.

## Notes

- Design (Lancet 2023): 770 patients at 187 sites in 18 countries randomised between February 2020 and August 2021 to NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, fluorouracil 2,400 mg/m2 over 46 hours, days 1 and 15 of 28) or nab-paclitaxel 125 mg/m2 with gemcitabine 1,000 mg/m2 on days 1, 8 and 15. Median follow-up 16.1 months. Label figures (Onivyde, openFDA): overall survival 11.1 against 9.2 months (hazard ratio 0.84, 0.71 to 0.99; p 0.0403), progression-free survival 7.4 against 5.6 months (hazard ratio 0.70; p 0.0001), response 41.8 against 36.2 percent (not significant). Grade 3 or worse treatment-emergent adverse events 87 against 86 percent; treatment-related deaths 6 (2 percent) against 8 (2 percent). FDA approval of the regimen 13 February 2024; EU indication listed on the Onivyde product page; NICE appraisal TA1052 terminated on 2 April 2025 without a company submission.
- UK sites (registry, 6): Guy's and St Thomas' NHS Foundation Trust; Royal Marsden (two entries); Imperial College Healthcare; the Christie; Nottingham City Hospital.

## Sources

- ClinicalTrials.gov NCT04083235: https://clinicaltrials.gov/study/NCT04083235
- Wainberg et al., NAPOLI 3 (Lancet 2023): https://doi.org/10.1016/S0140-6736(23)01366-1
- Onivyde label (openFDA): NAPOLI 3 results table: https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22ONIVYDE%22

## Connected records

- cancers: [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Platinum agents](https://onco.cc/technologies/platinum/), [Topoisomerase-I inhibitors (and ADC payloads)](https://onco.cc/technologies/topoisomerase-inhibitors/)
- drugs: [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Liposomal irinotecan](https://onco.cc/drugs/liposomal-irinotecan/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/)
- companies: [Ipsen](https://onco.cc/companies/ipsen/)
- trials: [CanStem111P](https://onco.cc/trials/canstem111p/), [MPACT](https://onco.cc/trials/mpact/), [NAPOLI-1](https://onco.cc/trials/napoli-1/), [PRODIGE 4 / ACCORD 11](https://onco.cc/trials/prodige-4-accord-11/)
- people: [Zev A. Wainberg](https://onco.cc/people/zev-wainberg/)
- key papers: [Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial](https://onco.cc/key-papers/paper-napoli-1-nanoliposomal-irinotecan-lancet-2016/), [Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up](https://onco.cc/key-papers/paper-esmo-pancreatic-cancer-guideline-ann-oncol-2023/)
- roadmaps: [Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs](https://onco.cc/roadmaps/chemotherapy-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/)

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