NAPOLI-3 Post Hoc Review Highlights Long-Term Survival With NALIRIFOX in PDAC

A post hoc analysis of NAPOLI-3 reveals clinical characteristics and treatment strategies associated with long-term survival in patients with metastatic PDAC treated with NALIRIFOX.

New insights from a post hoc analysis of the phase 3 NAPOLI-3 study (NCT04083235) highlight the clinical profiles, like dose modifications, of long-term survivors with metastatic pancreatic ductal adenocarcinoma (PDAC) who received NALIRIFOX, according to a presentation from the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Of the patients from centers in North America who received NALIRIFOX in the trial (n = 120), 15 had an overall survival (OS) of at least 18 months, and thus, were determined to be long-term survivors. The median OS in this group was 19.5 months (IQR, 18.8-22.6).

These patients had a median age of 61.0 years (IQR, 49.0-70.5), 46.7% were female, and 66.7% were White. With regard to baseline characteristics, 53.3% had an ECOG performance status of 0, had the main pancreatic tumor located in the body of the pancreas (53.3%), and a median CA 19-9 level of 166.8 U/mL (IQR, 32.7-1728.4). Moreover, 86.7% of patients had metastatic disease at diagnosis and 53.3% had at least 3 metastatic sites, most of which were in the liver (40.0%). The majority of these patients had an UGT1A1*28 allele status that was non-homozygous (73.3%).

With regard to treatment patterns, most of the patients in this group experienced dose reductions (66.7%) and delays (86.7%) of liposomal irinotecan (Onivyde), as well as oxaliplatin (80%; 80%).

“A substantial proportion of long-term survivors had [at least] 3 metastatic sites at baseline, but they otherwise had a good clinical profile: younger (vs typical mPDAC diagnosis), few tumors in the head or tail of the pancreas, a good performance status, and reasonably low CA 19-9 levels,” lead study author Vincent Chung, MD, medical oncologist of City of Hope, in Duarte, CA, and colleagues, wrote in a poster. “Owing to the small sample size, these results should be interpreted with caution.”

Looking Closely at NAPOLI-3: Design, Prior Data, and the Road Leading Up to the Current Analysis

The open-label, randomized, phase 3 study enrolled patients (n = 770) with confirmed PDAC that had not previously been treated in the metastatic setting. These patients were at least 18 years of age and had a metastatic disease diagnosis up to 6 weeks before screening, at least 1 measurable metastatic lesion per CT/MRI and RECIST criteria, and an ECOG performance status no higher than 1.

Patients were randomly assigned 1:1 to receive 1000 mg/m² of gemcitabine plus 125 mg/m² of nab-paclitaxel (Abraxane) on days 1, 8, and 15 of a 28-day cycle vs NALIRIFOX, which is comprised of 50 mg/m² of liposomal irinotecan plus 2400 mg/m² of 5-FU, 400 mg/m² of leucovorin, and 60 mg/m² of oxaliplatin on days 1 and 15 of a 28-day cycle. Treatment continued until progressive disease, intolerable toxicity, or withdrawal from the study. Stratification factors included performance status (0 vs 1), geographic region, and liver metastases. The primary end point of the study was OS in the intention-to-treat population.²

Prior data from the trial showed that at a median follow-up of 16.1 months (IQR, 13.4-19.1), the median OS was 11.1 months (95% CI, 10.0-12.1) with NALIRIFOX (n = 383) vs 9.2 months (95% CI, 8.3-10.6) with gemcitabine/nab-paclitaxel (n = 387; HR, 0.83; 95% CI, 0.70-0.99; P = .036). The regimen also improved median progression-free survival (PFS) over gemcitabine/nab-paclitaxel, at a median of 7.4 months (95% CI, 6.0-7.7) and 5.6 months (95% CI, 5.3-5.8), respectively (HR, 0.70; 95% CI, 0.59-0.85; P = .0001). The objective response rates in the respective arms were 41.8% (95% CI, 36.8%-46.9%) and 36.2% (95% CI, 31.4%-41.2%).

These data supported the FDA’s decision to approve NALIRIFOX for use as a first-line treatment in patients with metastatic pancreatic adenocarcinoma in February 2024.³

For this specific post hoc analysis, investigators set out to describe the characteristics of long-term survivors among the North American population of patients who received NALIRIFOX in the trial.¹ They also wanted to gain insights on clinical and pathological features that could be linked with extended survival with the regimen.

Looking at the Latest Post Hoc Analysis

For the analysis shared via poster at the meeting, investigators looked at data from patients enrolled at 70 centers across North America. They evaluated baseline characteristics and dosing patterns for NALIRIFOX in those who survived at least 18 months. The analysis that they performed was purely descriptive with no comparisons or statistical tests performed. They utilized Kaplan-Meier methods to estimate median OS.

For long-term survivors, the median cumulative dose of liposomal irinotecan was 1229.4 mg/m² (IQR, 821.9-1513.9 mg/m²) and the median cumulative dose of oxaliplatin was 962.3 mg/mL (IQR, 655.0-1470.3 mg/mL). The median duration of exposure for the respective drugs was 65.1 weeks (IQR, 40.1-89.0) and 39.9 weeks (IQR, 26.6-76.4).

Disclosures: Chung disclosed serving in a consulting or advisory role for Perthera, and having received research funding from Merck.

References

1. Chung V, Kochenderfer M, Natarajan N, et al. NAPOLI 3 phase 3 trial of NALIRIFOX in metastatic pancreatic ductal adenocarcinoma: characteristics of long-term survivors. J Clin Oncol. 2025;43(suppl 17):LBA4175. doi:10.1200/JCO.2025.43.17_suppl.LBA4175
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. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed May 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma