NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

Author(s): Zev A. Wainberg, Davide Melisi, Teresa Macarulla, Roberto Pazo-Cid, Sreenivasa R Chandana, Christelle De La Fouchardiere, Andrew Peter Dean, Igor Kiss, Woojin Lee, Thorsten Oliver Goetze, Eric Van Cutsem, Andrew Scott Paulson, Tanios S. Bekaii-Saab, Shubham Pant, Richard Hubner, Zhimin Xiao, Huanyu Chen, Fawzi Benzaghou, Eileen Mary O’Reilly
Source: J Clin Oncol 41, 2023 (suppl 4; abstr LBA661) 10.1200/JCO.2023.41.3_suppl.LBA661
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

The NAPOLI-3 study assessed FOLFOX+ liposomal irinotecan vs. gemcitabine + nab-paclitaxel. NALIRIFOX was superior, with an OS of 11.1 vs. 9.2 months. Criticisms of modern gem trials are often that of rigid dosing requirements that differ from modern clinical practice. Additionally, it is unclear whether NALIRIFOX provides any meaningful benefit over FOLFIRINOX, and the cost is always a consideration.


Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC.


Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025.


Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%).


First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235.

Author Affiliations

UCLA Medical Center–Santa Monica, Santa Monica, CA; , Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; , Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain; , Hospital Universitario Miguel Servet, Zaragoza, Spain; , Western Michigan Cancer Center, Kalamazoo, MI; , Medical Oncology Department, Centre Leon Berard, Lyon I University, Lyon, France; , St. John of God Hospital, Subiaco, Australia; , Masarykuv onkologicky usta, Brno, Czech Republic; , Center for Breast Cancer, National Cancer Center, Goyang, South Korea; , Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest, and Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany; , University of Leuven, Leuven, Belgium; , Texas Oncology PA, Dallas, TX; , Mayo Clinic Cancer Center Scottsdale, Phoenix, AZ; , The University of Texas MD Anderson Cancer Center, Houston, TX; , Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK, Manchester, United Kingdom; , Ipsen Corp, Cambridge, MA; , IPSEN, Paris, France; , Memorial Sloan Kettering Cancer Center, New York, NY;

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