A late-breaking post-hoc analysis of the Phase III NAPOLI 3 study presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting has identified key characteristics associated with long-term survival in patients with metastatic pancreatic adenocarcinoma (mPDAC) treated with the NALIRIFOX regimen. The analysis found that long-term survivors achieved a median overall survival of 19.5 months, providing crucial insights for managing one of the most challenging cancers to treat.
Study Design and Patient Population
The NAPOLI 3 trial represents the largest interventional study in metastatic pancreatic adenocarcinoma with the longest follow-up period. The post-hoc analysis focused on 15 patients who survived 18 months or longer out of 120 patients treated with the NALIRIFOX regimen (Onivyde plus oxaliplatin, fluorouracil and leucovorin) as first-line therapy.
The broader NAPOLI 3 study enrolled 770 patients across 187 trial sites in 18 countries, randomizing patients to receive either the NALIRIFOX regimen (n=383) administered twice monthly or nab-paclitaxel and gemcitabine (n=387) given three times monthly.
Key Survival Characteristics
Long-term survivors demonstrated a median overall survival of 19.5 months with an interquartile range of 18.8-22.6 months. Several clinical and pathological factors distinguished these patients from the broader population.
Age emerged as a significant factor, with long-term survivors having a median age of 61.0 years (IQR: 49.0-70.5) at diagnosis, younger than the typical patient population. Tumor location also played a crucial role, with 53.3% of long-term survivors having their primary pancreatic tumor located in the body of the pancreas, rather than the head or tail.
Paradoxically, many long-term survivors presented with extensive disease at diagnosis. A substantial proportion (66.7%) had liver metastasis, and 53.3% had three or more metastatic sites, suggesting that disease burden alone may not determine long-term outcomes.
Treatment Management and Dosing Strategies
The analysis revealed that dose modifications played a critical role in enabling long-term survival. Dose reductions and treatment delays for managing adverse events allowed patients to stay on treatment longer and achieve higher cumulative doses of both liposomal irinotecan and oxaliplatin.
"Liver metastasis and ≥3 metastatic sites, dose modifications and an otherwise good clinical profile enabled people to achieve a long mOS," according to the study findings. This suggests that proactive management of treatment-related toxicities through dose adjustments may be more beneficial than maintaining full doses at the expense of treatment discontinuation.
Clinical Context and Significance
Pancreatic adenocarcinoma represents one of the most aggressive malignancies, with more than 60,000 people diagnosed annually in the U.S. and nearly 500,000 globally. The disease is typically detected after metastasis has occurred, and fewer than 20% of patients with metastatic disease survive longer than one year. Pancreatic cancer has the lowest five-year survival rate among all cancer types.
Dr. Vincent Chung, Medical Oncologist at City of Hope, emphasized the clinical relevance: "When people are diagnosed with metastatic pancreatic adenocarcinoma, the most important question remains: how long will they have with their loved ones. Findings from the NAPOLI 3 post-hoc analysis provide important context on long-term overall survival with the Onivyde (NALIRIFOX) treatment regimen."
Treatment Regimen Details
Onivyde is a long-circulating liposomal formulation of irinotecan, a topoisomerase inhibitor. The drug is enclosed in liposomes that accumulate in tumors and release the active compound slowly over time. The NALIRIFOX regimen combines Onivyde with oxaliplatin, fluorouracil, and leucovorin, administered via intravenous infusion over 90 minutes every two weeks.
Sandra Silvestri, MD, PhD, Executive Vice President and Chief Medical Officer at Ipsen, noted the historical significance: "Data from the Phase III NAPOLI 3 trial were the first positive data of its kind in a decade and continue to reinforce the potential for long-term outcomes with the Onivyde (NALIRIFOX) regimen. With people on average living just 4-6 months following diagnosis with pancreatic adenocarcinoma, these data help us to understand the characteristics associated with long-term survival."
Study Limitations and Future Directions
The researchers acknowledged important limitations in interpreting these results, noting that this was a post-hoc analysis with a small sample size of only 15 long-term survivors. While the findings provide valuable insights into factors associated with extended survival, larger prospective studies would be needed to validate these observations and develop predictive models for patient selection.
The analysis represents an important step forward in understanding which patients with metastatic pancreatic adenocarcinoma may benefit most from the NALIRIFOX regimen and how treatment modifications can optimize outcomes in this challenging patient population.
