On February 13, 2024, the U.S. Food and Drug Administration approved liposomal irinotecan (Onivyde) for use with oxaliplatin, fluorouracil, and leucovorin in the first-line treatment of metastatic pancreatic adenocarcinoma.1
Supporting Efficacy Data
Approval was based on the open-label NAPOLI 3 trial (ClinicalTrials.gov identifier NCT04083235), in which 770 patients who had received no chemotherapy in the metastatic setting were randomly assigned to receive the following treatments:
- NALIRIFOX: Liposomal irinotecan at 50 mg/m2, oxaliplatin at 60 mg/m2, leucovorin at 400 mg/m2, and fluorouracil at 2,400 mg/m2 over 46 hours every 2 weeks
- Gem+NabP: Nab-paclitaxel at 125 mg/m2 and gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 of 28-day cycles.
The median overall survival was 11.1 months (95% confidence interval [CI] = 10.0–12.1 months) in the NALIRIFOX group vs 9.2 months (95% CI = 8.3–10.6 months) in the Gem+NabP group (hazard ratio [HR] = 0.84, 95% CI = 0.71–0.99, P = .0403). Median progression-free survival was 7.4 months (95% CI = 6.0–7.7 months) vs 5.6 months (95% CI = 5.3–5.8 months; HR = 0.70, 95% CI = 0.59–0.85, P = .0001). An objective response was observed in 41.8% vs 36.2% of patients.
How It Is Used
The recommended liposomal irinotecan dose is 50 mg/m2 via intravenous infusion over 90 minutes every 2 weeks. Liposomal irinotecan should be administered before oxaliplatin, fluorouracil, and leucovorin on the same day. There is no recommended dosage of liposomal irinotecan for patients with serum bilirubin above the upper limit of normal. Concomitant use with strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin) and strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, diltiazem) should be avoided.
Safety Profile
In NAPOLI 3, the most common adverse events of any grade in the NALIRIFOX group with a ≥ 5% higher incidence vs the Gem+NabP group included diarrhea (72%) fatigue (62%), nausea (59%), vomiting (40%), decreased appetite (37%), and abdominal pain (35%). The most common grade 3 or 4 adverse events included diarrhea (22%), fatigue (15%), nausea (12%), decreased appetite (9%), and embolism (7%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (26%) and decreased potassium (22%).
OF NOTE
Liposomal irinotecan has a boxed warning for severe neutropenia and severe diarrhea. It also has warnings/precautions for interstitial lung disease, severe hypersensitivity reaction, and embryofetal toxicity.
Serious adverse events occurred in 54% of the NALIRIFOX group, most commonly infections including COVID-19 (14%), diarrhea (9%), and vomiting (6%). Liposomal irinotecan was discontinued because of adverse events in 17% of patients, including neutropenia, thrombocytopenia, diarrhea, fatigue, infections, and cerebrovascular accident. Adverse events led to death in 6% of patients, including cerebrovascular accident, hemorrhage, pneumonia, sepsis, and sudden death.
Liposomal irinotecan has a boxed warning for severe neutropenia and severe diarrhea. It also has warnings/precautions for interstitial lung disease, severe hypersensitivity reaction, and embryofetal toxicity. It is contraindicated in patients with severe hypersensitivity reaction to liposomal irinotecan or other forms of irinotecan hydrochloride. Patients should be advised not to breastfeed while receiving liposomal irinotecan.
REFERENCE
1. Onivyde (irinotecan liposome injection), for intravenous use, prescribing information, Ipsen Biopharm Ltd, February 2023. Accessed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/207793s016lbl.pdf. Available February 26, 2024.
