Frontline NALIRIFOX Regimen Improves OS in Metastatic Pancreatic Ductal Adenocarcinoma

The NALIRIFOX regimen significantly improved overall survival over nab-paclitaxel plus gemcitabine in previously untreated patients with metastatic pancreatic ductal adenocarcinoma, meeting the primary end point of the phase 3 NAPOLI 3 trial.

Pancreatic cancer

Pancreatic Ductal Adenocarcinoma

The NALIRIFOX regimen comprised of irinotecan liposome injection (Onivyde), 5-fluorouracil (5-FU)/leucovorin, and oxaliplatin significantly improved overall survival (OS) over nab-paclitaxel (Abraxane) plus gemcitabine in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC), meeting the primary end point of the phase 3 NAPOLI 3 trial (NCT04083235).1

The regimen was also found to significantly improve progression-free survival (PFS) vs nab-paclitaxel and gemcitabine. The toxicity profile of the investigative combination proved to align with what had been reported in a prior phase 1/2 study.

In light of the news, Ipsen announced plans to file a supplemental new drug application seeking the approval of the regimen in this patient population in the United States.

“The positive results from the NAPOLI 3 trial demonstrate that compared with the standard of care, the investigation Onivyde treatment regimen extended the lives of people living with metastatic PDAC who were previously untreated,” Howard Mayer, executive vice president and head of research and development for Ipsen, stated in a press release.

Previously, the combination of liposomal irinotecan and 5-FU/leucovorin was approved by the FDA for use in patients with metastatic PDAC after progression with gemcitabine-based treatment.2 The regulatory decision was supported by findings from the phase 3 NAPOLI-1 trial (NCT01494506), in which the regimen significantly prolonged survival vs 5-FU/leucovorin alone (HR, 0.67; P = .012).3

Data from an ongoing phase 2 study (NCT02551991) exploring the NALIRIFOX regimen in patients with previously untreated, locally advanced or metastatic PDAC indicated that the combination had encouraging antitumor activity in the frontline setting.4 With NAPOLI-3, investigators set out to further evaluate the safety and efficacy of the regimen in this setting.

The open-label, randomized, multicenter, phase 3 trial enrolled patients with a histologically or cytologically confirmed adenocarcinoma who had not received prior treatment.4 An initial diagnosis of metastatic disease must have happened up to 6 weeks prior to screening and patients were required to have at last 1 metastatic tumor that was measurable via CT scan or MRI.

Patients also needed to be at least 18 years of age; have an ECOG performance status of 0 or 1 both at the time of screening and in the week prior to randomization; and acceptable hematologic, hepatic, and renal functions.

Exclusion criteria included having received prior treatment, having only localized advanced disease, a history of central nervous system metastases, clinically significant gastrointestinal disorders, a history of any second malignancy in the past 2 years, or neuroendocrine or acinar pancreatic carcinoma.

Participants were randomly assigned 1:1 to receive liposomal irinotecan at 50 mg/m2 free base plus 5-FU at 2400 mg/m2 and leucovorin at 400 mg/m2 plus oxaliplatin at 60 mg/m2 (target, n = 375) or nab-paclitaxel at 125 mg/m2 plus gemcitabine at 1000 mg/m2. Treatment in the investigative arm was given on days 1 and 15 of each 28-day cycle; in the control arm, the combination was administered on days 1, 8, and 15 of each 28-day cycle.

Treatment will continue until progressive disease, intolerable toxicity, or patient withdrawal.

Stratification factors include performance status (0 vs 1), region (North America vs East Asia vs other), and the presence of liver metastases (yes vs no).

In addition to the primary outcome measure of OS, key secondary outcome measures included PFS, objective response rate, quality-of-life assessment, incidence of treatment-emergent adverse effects (AEs), serious AEs, and laboratory abnormalities.1

“The prognosis for people diagnosed with pancreatic cancer is extremely poor and we plan to submit these new findings to the regulatory authority as, if approved, we believe this regimen could offer up an important new treatment option for people living with an aggressive and hard-to-treat cancer,” Mayer added in the press release.1

Data from NAPOLI 3 will be shared at an upcoming medical meeting.1


  1. Onivyde regimen demonstrated statistically significant improvement in overall survival in previously untreated metastatic pancreatic ductal adenocarcinoma. News release. Ipsen Biopharmaceuticals, Inc. November 9, 2022. Accessed November 9, 2022.
  2. Onivyde (irinotecan liposome injection). Prescribing information; Ipsen Biopharmaceuticals, Inc.; 2017. Accessed November 9, 2022.
  3. Wang-Gillam A, Li C-P, Bodoky G, et al. 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. Lancet. 2016;387(10018):545-557. doi:10.1016/S0140-6736(15)00986-1
  4. Wainberg ZA, Bekaii-Saab T, Hubner R, et al. NAPOLI-3: an open-label, randomized, phase III study of first-line liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin versus nab-paclitaxel + gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2020;38(suppl 15):TPS4661. doi:10.1200/JCO.2020.38.15_suppl.TPS4661
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