FDA Accepts sNDA for Frontline NALIRIFOX in Metastatic Pancreatic Ductal Adenocarcinoma

The FDA has accepted a supplemental new drug application (sNDA) seeking approval of the NALIRIFOX regimen comprised of irinotecan liposome injection (Onivyde) plus 5-fluorouracil (5-FU), leucovorin, and oxaliplatin as a first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).¹

The sNDA was supported by data from the phase 3 NAPOLI 3 trial (NCT04083235), which showed that NALIRIFOX provided a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) vs nab-paclitaxel (Abraxane) plus gemcitabine.²

Findings presented at the 2023 Gastrointestinal Cancers Symposium demonstrated that at a median follow-up of 16.1 months (95% CI, 15.3-16.8), patients in the NALIRIFOX arm (n = 383) experienced a median OS of 11.1 months (95% CI, 10.0-12.1) vs 9.2 months (95% CI, 8.3-10.6) for those in the nab-paclitaxel/gemcitabine arm (n = 387; HR, 0.83; 95% CI, 0.70-0.99; P = .04). The 12-month OS rates were 45.6% for NALIRIFOX vs 39.5% for nab-paclitaxel/gemcitabine, and the 18-month OS rates were 26.2% and 19.3%, respectively.¹

Furthermore, NALIRIFOX resulted in a median PFS of 7.4 months (95% CI, 6.0-7.7) vs 5.6 months (95% CI, 5.3-5.8) with nab-paclitaxel/gemcitabine in this population (HR, 0.69; 95% CI, 0.58-0.83; P < .0001).²

The FDA has set a target action date of February 13, 2024, under the Prescription Drug User Fee Act.¹

“PDAC is a devastating disease in need of additional treatment options. The FDA’s decision to accept the sNDA for [NALIRIFOX] in treatment-naïve patients with metastatic disease represents an important milestone in the potential treatment of this complex form of cancer,” Howard Mayer, executive vice president and head of Research and Development at Ipsen Biopharmaceuticals, stated in a news release.¹ “We’re committed to developing therapies which have the potential to make a meaningful difference to the lives of people living with cancer and look forward to working with FDA as they review this application.”

NAPOLI 3 is an open-label, multicenter, randomized phase 3 study that enrolled patients with confirmed metastatic PDAC who were previously untreated in the metastatic setting.3 Key inclusion criteria included 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, an ECOG performance status of 0 or 1, and adequate hepatic and renal function.

Patients were excluded if they had any prior treatment for pancreatic cancer in the metastatic setting, including any surgery, radiotherapy, chemotherapy, or investigational therapy; adjuvant chemotherapy within 12 months of study treatment; only locally advanced disease; or a known history of central nervous system metastases.

Investigators randomly assigned patients 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.²

Along with the primary end point of OS, secondary end points included PFS, overall response rate, and safety.

Additional data showed that patients treated with NALIRIFOX achieved an ORR of 41.8% (95% CI, 36.8%-46.9%), including a complete response (CR) rate of 0.3%, 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%. The ORR was 36.2% (95% CI, 31.4%-41.2%) for nab-paclitaxel/gemcitabine, including CR, PR, SD, and PD rates of 0.3%, 35.9%, 26.1%, and 14.5%, respectively. Notably, 22.5% and 23.3% of patients from the NALIRIFOX and nab-paclitaxel/gemcitabine arms, respectively, were not evaluable for response.²

Regarding safety, the toxicity of NALIRIFOX was consistent with the safety profiles observed with its individual components. The most common grade 3/4 treatment-emergent adverse effects reported in at least 10% of patients in the investigative and control arms, respectively, included diarrhea (20.3% for NALIRIFOX and 4.5% for nab-paclitaxel/gemcitabine), nausea (11.9% and 2.6%), hypokalemia (15.1% and 4.0%), anemia (10.5% and 17.4%) and neutropenia (14.1% and 24.5%).¹

References

1. 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 14, 2023. https://www.ipsen.com/press-releases/
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
3. 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 14, 2023. https://clinicaltrials.gov/ct2/show/NCT04083235