FDA Accepts sNDA for Frontline NALIRIFOX Combo in Metastatic PDAC

The FDA has accepted a supplemental new drug application (sNDA) for injectable irinotecan liposome (Onivyde) in combination with 5-fluorouracil/leucovorin (5-FU) and oxaliplatin (NALIRIFOX) in the frontline treatment of patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to a press release from Ipsen.¹

The regulatory agency has set a Prescription Drug User Fee Act date of February 13, 2024 to make a decision on the sNDA for NALIRIFOX in this indication.

“The FDA’s decision to accept the sNDA for this [irinotecan liposome injection]–based regimen 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, said in the press release. “We’re committed to developing therapies [that] 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.”

Supporting data for this sNDA came from the phase 3 NAPOLI 3 trial (NCT04083235), in which investigators compared the efficacy of the NALIRIFOX regimen with that of nab-paclitaxel plus gemcitabine among those with metastatic PDAC.

Findings presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting indicated that the median overall survival (OS) was 11.1 months (95% CI, 10.0-12.1) with NALIRIFOX vs 9.2 months (95% CI, 8.3-10.6) with gemcitabine plus nab-paclitaxel (Hazard ratio [HR], 0.83; 95% CI, 0.70-0.99; P = .04).² The OS rates at 12 months and 18 months were 45.6% (95% CI, 40.5%-50.5%) vs 39.5% (95% CI, 34.6%-44.4%), and 26.2% (95% CI, 20.9%-31.7%) vs 19.3% (95% CI, 14.8%-24.2%) in each respective arm.

Based on investigator assessment, the median progression-free survival (PFS) was 7.4 months (95% CI, 6.0-7.7) in the experimental arm vs 5.6 months (95% CI, 5.3-5.8) in the comparator arm (HR, 0.69; 95% CI, 0.58-0.83; P <.0001). Additionally, the 12-month and 18-month PFS rates in each respective arm were 27.4% (95% CI, 22.3%-32.7%) vs 13.9% (95% CI, 9.7%-18.9%) and 11.4% (95% CI, 7.1%-16.9%) vs 3.6% (95% CI, 0.5%-12.3%).

“These results support NALIRIFOX as a treatment reference regimen in frontline untreated pancreas cancer,” lead author Eileen M. O'Reilly, MD, Winthrop Rockefeller Endowed Chair of Medical Oncology; co-director of Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research; and section head of Hepatopancreatobiliary and Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center, said in a presentation on the findings.

Investigators of the phase 3 NAPOLI 3 trial randomly assigned 770 patients 1:1 to either receive the NALIRIFOX (n = 383) or control (n = 387) regimens. In the experimental arm, patients received 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 all 28-day cycles. In the control arm, patients received 1000 mg/m² of gemcitabine plus 125 mg/m² of nab-paclitaxel on day 1, 8, and 15 of every 28-day cycle.

The primary end point of the trial was PFS. Secondary end points included PFS, overall response rate, and safety.

Patients 18 years and older with confirmed PDAC not previously treated in the metastatic setting were eligible for enrollment on the trial. Additional eligibility criteria included having 1 or more measurable lesions per RECIST v1.1 criteria as well as an ECOG performance status of 0 or 1.

High-grade hematologic treatment-emergent adverse effects (TEAEs) in the NALIRIFOX and control arms, respectively, included neutropenia (26.2% vs 40.4%), anemia (10.5% vs 17.4%), and thrombocytopenia (1.6% vs 6.1%). Additionally, grade 3/4 non-hematologic TEAEs in each arm included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), and vomiting (7.0% vs 2.1%).

References

1. Ipsen announces U.S. FDA submission acceptance of its supplemental new drug application for Onivyde regimen in first-line metastatic pancreatic ductal adenocarcinoma. News release. Ipsen. June 14, 2023. Accessed June 15, 2023. bit.ly/3NdqcVB
2. O’Reilly EM, Melisi D, Macarulla T, et al. Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial. J Clin Oncol. 2023;41(suppl 16):4006. doi:10.1200/JCO.2023.41.16_suppl.4006