Dose Reductions of Liposomal Irinotecan, Oxaliplatin Are Not Associated With Worsened OS in Metastatic PDAC

Liposomal irinotecan (Onivyde) and oxaliplatin dose reductions were not associated with a negative impact on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) treated with NALIRIFOX (liposomal irinotecan, oxaliplatin, 5-fluorouracil [5-FU], and leucovorin), according to findings from an exploratory post hoc analysis of the phase 3 NAPOLI 3 trial (NCT04083235) presented at the 2025 Gastrointestinal Cancers Symposium.

Findings showed that among patients in the NALIRIFOX arm who were part of the safety population (n = 370), those who required dose reductions of liposomal irinotecan (n = 194) achieved a median OS of 12.6 months (95% CI, 11.0-14.5) compared with 9.4 months (95% CI, 7.5-11.5) in patients without a dose reduction of the agent (n = 176). Similarly, dose reductions of oxaliplatin (n = 217) were associated with a median OS of 13.5 months (95% CI, 11.7-15.2) compared with 7.7 months (95% CI, 6.2-10.2) in patients who did not receive a dose reduction of oxaliplatin (n = 153).

Similar OS results were seen when looking at subgroups of patients treated in North America and the rest of the world.

"These results of this post hoc analysis suggest that liposomal irinotecan or oxaliplatin dose reductions [did] not adversely affect OS,” lead study author, Anjan J. Patel, MD, an oncologist and hematologist with Florida Cancer Specialists and Research Institute in Sarasota, Florida, said in a presentation of the data. “These data suggest a path forward to further optimize the OS of patients with metastatic PDAC receiving NALIRIFOX.”

Prior data from NAPOLI 3 supported the February 2024 FDA approval of NALIRIFOX for the frontline treatment of patients with metastatic pancreatic adenocarcinoma.2

Trial Design

The exploratory post hoc analysis of the NAPOLI 3 trial evaluated the impact of dose reductions of liposomal irinotecan and oxaliplatin on OS in patients with metastatic PDAC treated with NALIRIFOX.

This randomized, open-label, phase 3 study enrolled patients 18 years of age or older with metastatic PDAC not previously treated in the metastatic setting. Eligible patients had an ECOG performance status of 0 or 1, confirmed metastatic disease diagnosed within 6 weeks of screening, and at least 2 measurable metastatic lesions by RECIST 1.1 criteria.

Patients were randomly assigned 1:1 to receive NALIRIFOX consisting of liposomal irinotecan at 50 mg/m², 5-FU at 2400 mg/m², leucovorin at 400 mg/m², and oxaliplatin at 60 mg/m² on days 1 and 15 of each 28-day cycle; or gemcitabine at 1000 mg/m² plus nab-paclitaxel (Abraxane) at 125 mg/m² on days 1, 8, and 15 of each cycle. Tumor assessments were conducted every 8 weeks per RECIST 1.1 criteria, and treatment continued until disease progression, unacceptable toxicity, or study withdrawal.

Patient Demographics

The median age was 64.0 years (range, 36.0-81.0) in patients who did not receive dose reductions of liposomal irinotecan and 65.0 years (range, 20.0-85.0) in those who required dose reductions of the agent. Women constituted 39.8% of the non-reduced group and 53.6% of the dose-reduced group. Patients with an ECOG performance status of 0 comprised 34.7% and 48.5% of the non-reduced and reduced groups, respectively. Liver metastases were present in 83.5% and 76.3% of patients, respectively, and patients with at least 3 metastatic sites accounted for 42.0% and 36.6% of the non-reduced and reduced groups, respectively.

When split by dose reductions of oxaliplatin, the median age was 64.0 years (range, 36.0-81.0) in the non-reduced group and 64.0 years(range, 20.0-85.0) in the reduced group. Women made up 37.9% of the non-reduced group and 53.5% of the dose-reduced group. An ECOG performance status of 0 was observed in 32.7% of non-reduced patients and 48.4% of reduced patients. Liver metastases were reported in 84.3% and 76.5% of the non-reduced and reduced groups, respectively, and at least 3 metastatic sites were present in 41.2% and 37.8% of patients, respectively.

Treatment Exposure and Cumulative Dose

Among patients in the safety population of the NAPOLI 3 trial who received liposomal irinotecan or oxaliplatin at any dose, the most common any-grade adverse effect (As) leading to dose reductions was diarrhea (40% for liposomal irinotecan; 36% for oxaliplatin) Grade 3 or higher diarrhea led to dose reduction of liposomal irinotecan in 38% of patients and reductions of oxaliplatin in 35% of patients treated in North America; these rates were 24% and 23%, respectively, in the rest of the world.

Patients with dose reductions had a median treatment exposure of 31.7 weeks (interquartile range [IQR], 17.1-51.7) for liposomal irinotecan and 30.0 weeks (IQR, 17.3-40.1) for oxaliplatin, compared with 10.6 weeks (IQR, 3.9-35.6) and 8.1 weeks (IQR, 2.9-23.0), respectively, for those without dose reductions. The cumulative median dose was also higher for patients with dose reductions at 536.0 mg/m² (IQR, 295.6-870.1) for liposomal irinotecan and 635.6 mg/m² (IQR, 360.5-907.3) for oxaliplatin, compared with 248.9 mg/m² (IQR, 100.0-760.0) and 239.9 mg/m² (IQR, 119.1-595.5), respectively, for those without reductions.

References

1. Patel A, Laursen A, Cockrum P, et al. Effect of dose adjustments on overall survival in patients with metastatic pancreatic ductal adenocarcinoma treated with NALIRIFOX: a post hoc analysis of NAPOLI 3. J Clin Oncol. 2025;43(suppl 4);716. doi:10.1200/JCO.2025.43.4_suppl.716
2. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed January 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma