A recent real-world retrospective cohort study presented at the 2025 ASCO Gastrointestinal Cancers Symposium suggests that first-line NALIRIFOX (liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin) may offer a survival advantage compared to FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). The analysis, which aligned with the phase 3 NAPOLI 3 trial (NCT04083235) eligibility criteria, highlights a critical comparison in treatment strategies for this aggressive cancer.
The real-world data showed that patients treated with FOLFIRINOX had a median overall survival (OS) of 9.1 months (95% CI, 7.8-10.9), while the NAPOLI 3 trial reported an OS of 11.1 months (95% CI, 10.0-12.1) with NALIRIFOX. The study also examined an all-comer cohort of mPDAC patients treated with first-line FOLFIRINOX, revealing a median OS of 9.0 months (95% CI, 8.5-9.3) between January 1, 2014, and February 29, 2024. A subgroup treated with modified FOLFIRINOX (mFOLFIRINOX) experienced a median OS of 8.6 months (95% CI, 7.3-10.5).
Study Design and Patient Characteristics
The real-world analysis utilized de-identified, patient-level, longitudinal data from the Flatiron Electronic Health Record. The study included three cohorts: an all-comer cohort of patients treated with first-line FOLFIRINOX, a trial-aligned cohort meeting NAPOLI 3 eligibility criteria, and a subgroup treated with mFOLFIRINOX. Modified FOLFIRINOX was defined as an initial irinotecan dose of 150 mg/m2 or lower, or a cumulative 5-FU dose of 2720 mg/m2 or lower during the first cycle.
The median age in the trial-aligned cohort was 65.0 years (IQR, 59.0-71.0), compared to 64.0 years (IQR, 58.0-70.0) in the all-comer cohort and 65.5 years (IQR, 60.0-72.0) in the mFOLFIRINOX cohort. Male patients constituted 54.3%, 57.9%, and 55.8% of each cohort, respectively, while White patients made up 66.7%, 64.8%, and 64.9%. The median time from metastatic diagnosis to the index date was approximately 3.0 weeks across all cohorts.
NAPOLI 3 Trial Context
The phase 3 NAPOLI 3 trial compared NALIRIFOX to nab-paclitaxel plus gemcitabine in treatment-naive mPDAC patients. The NALIRIFOX regimen consisted of liposomal irinotecan (50 mg/m2), oxaliplatin (60 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2400 mg/m2) administered sequentially. The standard-of-care arm received nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2).
Patients in the NALIRIFOX arm had a median age of 64.0 years (range, 20-85), with a majority being male (53%) and White (82%). Most patients had an ECOG performance status of 1 (58%), multiple metastatic sites (39%), liver metastases (80%), and elevated CA 19-9 levels (84%).
Implications and Future Directions
According to Paul Cockrum, PharmD, director of American Oncology HEOR at Ipsen Pharma, the NALIRIFOX regimen demonstrated numerically improved OS compared to FOLFIRINOX, including modified FOLFIRINOX, in the real-world setting. Cockrum and coauthors emphasized the need for further analyses adjusting for baseline characteristics to provide deeper insights into the comparative efficacy of these regimens. These findings underscore the importance of continuous evaluation and refinement of treatment strategies to improve outcomes for patients with metastatic pancreatic cancer.
