Frontline NALIRIFOX Approved by FDA in Metastatic PDAC

The approval is based on results from the phase 3 NAPOLI 3 trial (NCT04083235), which analyzed NALIRIFOX vs nab-paclitaxel and gemcitabine in metastatic pancreatic adenocarcinoma.

The News

The FDA has approved irinotecan liposome (Onivyde) in combination with 5-fluorouracil/leucovorin (5-FU) and oxaliplatin (NALIRIFOX) as first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).¹

Supporting Data

The approval is based on results from the phase 3 NAPOLI 3 trial (NCT04083235), which analyzed NALIRIFOX vs nab-paclitaxel and gemcitabine for patients in the aforementioned population.² Results were previously presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.³ 

The median follow-up was 16.1 months, and the median overall survival (OS) was 11.1 months (95% CI, 10.0-12.1) in the NALIRIFOX group vs 9.2 months (95% CI, 8.3-10.6) in the nab-paclitaxel/gemcitabine group (HR, 0.83; 95% CI, 0.70-0.99; P = .036).2 At 12 months, the OS rate was 45.6% (95% CI, 40.5%-50.5%) and 39.5% (95% CI, 34.6%-44.4%) between both groups, respectively. The OS rate at 18 months in the NALIRIFOX group was 26.2% (95% CI, 20.9%-31.7%) vs 19.3% (95% CI, 14.8%-24.2%) in the comparator arm.

The median progression-free survival (PFS) was 7.4 months (95% CI, 6.0-7.7) in the NALIRIFOX group and 5.6 months (95% CI, 5.3-5.8) in the nab-paclitaxel/gemcitabine group (HR, 0.69; 95% CI, 0.58-0.83; P <.0001). At 12 months, the PFS rate was 27.4% (95% CI, 22.3%-32.7%) vs 13.9% (95% CI, 9.7%-18.9%), and at 18 months it was 11.4% (95% CI, 7.1%-16.9%) vs 3.6% (95% CI, 0.5%-12.3%) between each respective arm.

An objective response was observed in 42% of patients in the NALIRIFOX group vs 36% in the comparator arm (P = .11). Patients had a median duration of response of 7.3 months (95% CI, 5.8-7.6) and 5.0 months (95% CI, 3.8-5.6) between both groups, respectively (HR, 0.67; 95% CI, 0.48-0.93).

NAPOLI 3 Trial Design

A total of 770 patients were randomly assigned 1:1 to receive a continuous intravenous infusion of 50 mg/m² of liposomal irinotecan, 60 mg/m² of oxaliplatin, 400 mg/m² of leucovorin, and 2400 mg/m² of fluorouracil over 46 hours on days 1 and 15; or 125 mg/m2 of nab-paclitaxel and 1000 mg/m² of gemcitabine given intravenously on days 1, 8, and 15 of a 28-day cycle. After permanent discontinuation of treatment, patients had a 30-day follow-up and then a long-term follow-up conducted every 2 months. Long-term follow-up included monitoring of survival status, loss to follow-up, withdrawal, or study closure.

The primary end point was OS, with secondary end points including PFS and ORR.

Safety Data

The median duration of treatment was 24.3 weeks with a median of 5 cycles in the NALIRIFOX group and 17.6 weeks with a median of 4 cycles in the comparator arm. Dose reductions occurred in 60% vs 54% in each group, respectively.

More than 99% of patients had treatment-emergent adverse effects (TEAEs) in the NALIRIFOX arm compared with 99% in the comparator arm. The most common TEAEs in each respective arm included diarrhea (20% vs 5%), nausea (12% vs 3%), decreased appetite (9% vs 3%), and vomiting (7% vs 2%).

TEAEs leading to discontinuation occurred in 32% of patients in the NALIRIFOX arm vs 30% in the comparator arm. Dose reductions due to TEAEs occurred in 56% vs 50%, serious TEAEs occurred in 54% vs 52%, and TEAEs leading to death occurred in 6% vs 6% between both respective arms.

The FDA accepted the supplemental new drug application for NALIRIFOX in metastatic PDAC in June 2023.⁴

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. News release. FDA. February 13, 2024. Accessed February 13, 2024. https://bit.ly/3HXITdz
2. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1
3. 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
4. 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 January 18, 2024. http://tinyurl.com/442ck4uy