FDA Accepts sNDA for First-Line NALIRIFOX in Metastatic PDAC


Data from the phase 3 NAPOLI 3 trial have led the FDA to accept a supplemental new drug application for NALIRIFOX in patients with metastatic pancreatic ductal adenocarcinoma

The FDA has accepted a supplemental new drug application (sNDA) for liposomal irinotecan (Onivyde), 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) as a first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).1

Findings from the phase 3 NAPOLI 3 trial (NCT04083235) support the sNDA as treatment with NALIRIFOX led to a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) vs nab-paclitaxel (Abraxane) plus gemcitabine in this patient population.2

At a median follow-up of 16.1 months (95% CI, 15.3-16.8), patients treated with NALIRIFOX (n = 383) had a median OS of 11.1 months (95% CI, 10.0-12.1) compared with 9.2 months (95% CI, 8.3-10.6) for those given nab-paclitaxel and gemcitabine (n = 387; HR, 0.83; 95% CI, 0.70-0.99; P = .04). In the NALIRIFOX arm, the median PFS was 7.4 months (95% CI, 6.0-7.7) vs 5.6 months (95% CI, 5.3-5.8) in the nab-paclitaxel/gemcitabine arm (HR, 0.69; 95% CI, 0.58-0.83; P < .0001).

Based on these data, the FDA has set a Prescription Drug User Fee Act action date of February 13, 2024.

“I think that this adds value for the pancreatic cancer community, and I think it helps us springboard into the future, because now we have a new reference regimen that we can use to add drugs and to look at other strategies to improve outcomes,” said Zev A. Wainberg, MD, in an interview with Targeted OncologyTM.

The open-label, multicenter, phase 3 NAPOLI 3 trial enrolled patients with confirmed metastatic PDAC who were previously untreated in the metastatic setting.3 Patients were required to have metastatic disease diagnosed no more than 6 weeks prior to screening, at least 1 metastatic lesion measurable by MRI or CT scan per RECIST v1.1 criteria, adequate hepatic, and renal function, and an ECOG performance status of 0 or 1.

In a 1:1 fashion, patients were randomly assigned 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. Patients continued treatment until disease progression, unacceptable toxicity, or study withdrawal.

The primary end point of the study was OS with secondary end points of PFS, overall response rate, and safety. Investigators also evaluated exploratory end points of health-related quality-of-life and biomarker assessments.

Additional data from the study showed that among patients treated with NALIRIFOX, the ORR was 41.8% (95% CI, 36.8%-46.9%). This included a complete response (CR) rate of 0.3% in both arms, and a partial response (PR) rate of 41.5%, a stable disease (SD) rate of 25.8%, and a progressive disease (PD) rate of 9.9% in the liposomal irinotecan/NALIRIFOX arm. Among patients treated with nab-paclitaxel/gemcitabine, the ORR was 36.2% (95% CI, 31.4%-41.2%), including PR a PR rate of 35.9%, SD rate of 26.1%, and PD rate of 14.5%, respectively.

The safety profile of NALIRIFOX was consistent with those observed with its individual components. The most common grade 3/4 treatment-emergent adverse events among at least 10% of patients in the NALIRIFOX arm vs nab-paclitaxel/gemcitabine arm were diarrhea (20.3% v 4.5%), nausea (11.9% v 2.6%), hypokalemia (15.1% v 4.0%), anemia (10.5% v 17.4%) and neutropenia (14.1% v 24.5%).


Ipsen announces US FDA submission acceptance of its supplemental new drug application for Onivyde regimen in first-line metastatic pancreatic ductal adenocarcinoma. News release. Ipsen Biopharmaceuticals. June 14, 2023. Accessed June 15, 2023. https://tinyurl.com/2my9cvyk

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

A study to assess the effectiveness and safety of irinotecan liposome injection, 5-fluorouracil/leucovorin plus oxaliplatin in patients not previously treated for metastatic pancreatic cancer, compared to nab-paclitaxel+gemcitabine treatment (NAPOLI 3). ClinicalTrials.gov. Updated March 13, 2023. Accessed June 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04083235

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