FDA Approves Frontline NALIRIFOX for Metastatic Pancreatic Adenocarcinoma


The FDA has approved irinotecan liposome (Onivyde) with oxaliplatin, fluorouracil, and leucovorin, for the frontline treatment of metastatic pancreatic adenocarcinoma.



The FDA has approved irinotecan liposome (Onivyde) with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (NALIRIFOX), for the frontline treatment of metastatic pancreatic adenocarcinoma.

The safety and efficacy of the regimen were examined in the phase 3 NAPOLI 3 study (NCT04083235). NALIRIFOX (n = 383) significantly improved overall survival (OS) vs gemcitabine and nab-paclitaxel (Abraxane; n = 387), at a median of 11.1 months (95% CI, 10.0-12.1) vs 9.2 months (95% CI, 8.3-10.6), respectively, translating to a 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.71-0.99; P = .0403).

The regimen also improved progression-free survival (PFS) over gemcitabine/nab-paclitaxel, at a median of 7.4 months (95% CI, 6.0-7.7) and 5.6 months (95% CI, 5.3-5.8), respectively, translating to a 30% reduction in the risk of disease progression or death (HR, 0.70; 95% CI, 0.59-0.85; P = .0001). Moreover, NALIRIFOX elicited an objective response rate (ORR) of 41.8% (95% CI, 36.8%-46.9%) vs 36.2% (95% CI, 31.4%-41.2%) with gemcitabine/nab-paclitaxel.

About NAPOLI 3

The open-label, multicenter, randomized phase 3 study enrolled those with confirmed metastatic PDAC who were previously untreated in the metastatic setting.2 Patients needed to have metastatic disease that was diagnosed no more than 6 weeks before screening, at least 1 metastatic lesion that was measurable by MRI or CT scan and RECIST v1.1 criteria, and an ECOG performance status of 0 or 1, as well as acceptable hepatic and renal function.

If patients previously received treatment for pancreatic cancer in the metastatic setting, including any surgery, radiotherapy, chemotherapy, or investigational therapy, they were excluded. They also could not have received adjuvant chemotherapy within 12 months of study treatment, have only locally advanced disease, or have a known history of central nervous system metastases.

Participants were randomly assigned 1:1 to receive 50 mg/m2 of liposomal irinotecan plus 2400 mg/m2 of 5-FU, 400 mg/m2 of leucovorin, and 60 mg/m2 of oxaliplatin on days 1 and 15 of each 28-day cycle, or 1000 mg/m2 of gemcitabine plus 125 mg/m2 of nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal.

The primary end point of the trial was OS, and secondary end points comprised PFS, ORR, and safety.

Safety Data

The most common adverse reactions experienced with NALIRIFOX that occurred in at least 20% of patients included diarrhea, fatigue, nausea, vomiting, reduced appetite, abdominal pain, mucosal inflammation, constipation, and decreased weight.1 The most common laboratory abnormalities included decreased neutrophils, decreased potassium, decreased lymphocytes, and decreased hemoglobin.


  1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed February 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
  2. Wainberg ZA, Melisi D, Macarulla T, et al. 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. J Clin Oncol. 2023;41(suppl 4):LBA661. doi:10.1200/JCO.2023.41.3_suppl.LBA661
Related Videos
Video 6 - "Patient Case 2: A 62-Year-Old Woman with Metastatic Rectal Cancer"
Video 5 - "Adverse Events Associated With TAS-102 Plus Bevacizumab in CRC"
Michael J. Overman, MD
Ilyas Sahin, assistant professor, Medicine, Department of Medicine, Division of Hematology & Oncology, University of Florida College of Medicine
Michael J. Overman, MD
Manish A. Shah, MD, director, Gastrointestinal Oncology Program, Weill Cornell Medicine; chief, Solid Tumor Service, co-director, Center for Advanced Digestive Disease, NewYork Presbyterian
Katrina S. Pedersen, MD, MS
Efrat Dotan, MD
In this fifth episode of OncChats: Leveraging Immunotherapy in GI Malignancies, Toufic Kachaamy, MD, of City of Hope, Sunil Sharma, MD, of City of Hope, and Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, discuss next steps for research, including vaccination strategies, personalized cellular therapies, and more.
In this fourth episode of OncChats: Leveraging Immunotherapy in GI Malignancies, experts discuss research efforts being made with organoids to address existing questions with immunotherapy and the exploration of multimodality approaches to improve outcomes.