NAPOLI-3: First-Line NALIRIFOX Regimen Improves Overall Survival in Metastatic Pancreatic Cancer

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In the phase III NAPOLI-3 trial in previously untreated patients with metastatic pancreatic cancer, the NALIRIFOX regimen significantly improved overall survival and progression-free survival over nab-paclitaxel plus gemcitabine. NALIRIFOX contains liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin. These results were presented by Zev Wainberg, MD, and colleagues at the 2023 ASCO Gastrointestinal Cancers Symposium (Abstract LBA661).

At a median follow-up of 16.1 months, NAPOLI-3 met its primary endpoint, demonstrating a statistically significant improvement in overall survival with NALIRIFOX. Median overall survival was 11.1 months with the NALIRIFOX regimen compared to 9.2 months with nab-paclitaxel and gemcitabine (hazard ratio [HR] = 0.83, P = .04). Progression-free survival and objective response rates were also improved, according to Dr. Wainberg, Professor of Medicine at the University of California, Los Angeles (UCLA) and Co-Director of the UCLA GI Oncology Program.

Zev Wainberg, MD

Zev Wainberg, MD

“For the first time, a clinical study in the first-line setting for metastatic pancreatic ductal adenocarcinoma demonstrated superior overall survival and progression-free survival for an investigational regimen when compared to standard-of-care treatment with nab-paclitaxel and gemcitabine” said Dr. Wainberg. “These results support the NALIRIFOX regimen as a new reference regimen.”

NAPOLI-3 Background and Details

Liposomal irinotecan is an investigational long-circulating, liposomal topoisomerase inhibitor that has been approved, in combination with fluorouracil and leucovorin, for patients with metastatic pancreatic cancer whose disease progresses after gemcitabine-based therapy. Previous early-phase studies have shown its benefit in the first-line setting when oxaliplatin is added to the regimen, and this was further evaluated in NAPOLI-3, Dr. Wainberg noted. 

The open-label randomized trial evaluated the NALIRIFOX regimen in 770 previously untreated patients with metastatic pancreatic ductal adenocarcinoma. The global study enrolled approximately 31% of patients from North America; 3% from Southeast Asia; and 66% from Eastern and Western Europe, South America, and Australia. Approximately 80% of patients had liver metastases; primary tumor location was the head of the pancreas in approximately 40%, and 83% of patients had elevated CA 19-9 at baseline.  

Patients were randomly assigned to receive the NALIRIFOX regimen or standard therapy. The NALIRIFOX regimen consisted of liposomal irinotecan at 50 mg/m2 combined with fluorouracil at 2,400 mg/m2, leucovorin at 400 mg/m2, and oxaliplatin at 60 mg/m2 on days 1 and 15 of a 28-day cycle. The control regimen was nab-paclitaxel at 125 mg/m2 and gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle.

Additional Endpoints Met

“Beginning at about 3 months, the overall survival curves separate slightly and stay slightly separated throughout the duration,” Dr. Wainberg pointed out.

In addition to the significant improvement in overall survival, patients treated with NALIRIFOX also had a statistically significant improvement in median progression-free survival, which was 7.4 months vs 5.6 months for nab-paclitaxel/gemcitabine (HR = 0.69, P < .0001). Objective response rates were also higher with NALIRIFOX—41.8% vs 36.2% with nab-paclitaxel/gemcitabine—progressive disease as best response was documented for 9.9% vs 23.3% of patients, respectively.

“The overall survival and progression-free survival benefits with NALIRIFOX vs nab-paclitaxel/gemcitabine were generally consistent regardless of performance status, region, or presence of liver metastases,” Dr. Wainberg noted.

Safety and Adverse Events

“The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. There were no significant differences in the two arms with respect to treatment-emergent adverse events—grade ≥ 3 or all grades. There were no significant differences with respect to serious treatment-emergent adverse events or treatment-emergent adverse events attributed to death caused by any of the components of the regimen. However, when one looks at the nuances of the toxicity profiles, we can see these two regimens have very different toxicity profiles,” Dr. Wainberg said.

The most common grade 3 or 4 treatment-emergent adverse events for patients in the NALIRIFOX vs nab-paclitaxel/gemcitabine arms were 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%). Peripheral neuropathy appeared to be less with NALIRIFOX (3.2% vs 5.8%), he added.

The study’s sponsor, Ipsen, plans to file a supplemental new drug application with the U.S. Food and Drug Administration based on the study results.

Disclosure: For full disclosures of the study authors, visit


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