An exploratory post hoc analysis of the phase 3 NAPOLI 3 trial indicates that dose reductions of liposomal irinotecan (Onivyde) and oxaliplatin do not negatively impact overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) treated with NALIRIFOX (liposomal irinotecan, oxaliplatin, 5-fluorouracil [5-FU], and leucovorin). The findings, presented at the 2025 Gastrointestinal Cancers Symposium, offer insights into optimizing treatment strategies for this challenging malignancy.
The NAPOLI 3 trial, a randomized, open-label, phase 3 study, enrolled patients aged 18 years or older with metastatic PDAC who had not previously received treatment in the metastatic setting. Patients were randomized 1:1 to receive either NALIRIFOX or gemcitabine plus nab-paclitaxel. The post hoc analysis specifically evaluated the impact of dose reductions of liposomal irinotecan and oxaliplatin on OS in patients treated with NALIRIFOX.
Impact of Dose Reductions on Overall Survival
The analysis included 370 patients in the NALIRIFOX arm. Among those who required dose reductions of liposomal irinotecan (n = 194), the median OS was 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).
"These results of this post hoc analysis suggest that liposomal irinotecan or oxaliplatin dose reductions [did] not adversely affect OS," said lead study author Anjan J. Patel, MD, an oncologist and hematologist with Florida Cancer Specialists and Research Institute in Sarasota, Florida. "These data suggest a path forward to further optimize the OS of patients with metastatic PDAC receiving NALIRIFOX."
Patient Characteristics and Treatment Exposure
The median age of patients was similar in both the dose-reduced and non-reduced groups for both liposomal irinotecan and oxaliplatin. However, a higher proportion of women and patients with an ECOG performance status of 0 were observed in the dose-reduced groups. Liver metastases were common in both groups. Diarrhea was the most common adverse event leading to dose reductions.
Patients with dose reductions had a longer median treatment exposure compared to those without dose reductions. The cumulative median dose was also higher for patients with dose reductions, indicating that they were able to continue treatment for a longer duration despite requiring dose adjustments.
Implications for Clinical Practice
The findings from this analysis suggest that dose reductions of liposomal irinotecan and oxaliplatin should not be automatically viewed as detrimental to patient outcomes. Instead, they may allow patients to stay on treatment longer, potentially leading to improved survival. These data support the optimization of NALIRIFOX dosing strategies to maximize efficacy while managing toxicity in patients with metastatic PDAC.
