NALIRIFOX Numerically Improves OS Vs FOLFIRINOX in Metastatic PDAC

A 3-cohort retrospective analysis compared patients who met eligibility for the NAPOLI 3 trial with all-comers treated with FOLFIRINOX for PDAC.

NALRIFOX (liposomal irinotecan, 5-fluorouracil [5-FU]/leucovorin, and oxaliplatin) elicited numerically improved overall survival (OS) compared with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) as a frontline treatment for patients with pancreatic ductal adenocarcinoma (PDAC), according to findings from a real-world analysis presented at the 2025 ASCO Gastrointestinal Cancer Symposium.¹

Results from the analysis showed that treatment with FOLFIRINOX in a trial-aligned cohort of patients who met the eligibility criteria for the phase 3 NAPOLI 3 trial (NCT04083235, n = 219) elicited a median OS of 9.1 months (95% CI, 7.8-10.9) compared with 11.1 months (95% CI, 10.0-12.1) with NALIRIFOX. Furthermore, the median OS was 9.0 months (95% CI, 8.5-9.3) for all-comer patients treated with first-line FOLFIRINOX for PDAC since January 1, 2014. An additional trial-aligned cohort treated with modified FOLFIRINOX experienced a median OS of 8.6 months (95% CI, 7.3-10.5).

“[The] NALIRIFOX regimen in the NAPOLI 3 trial showed numerically improved OS compared to [FOLFIRINOX], including [modified FOLFIRINOX] in the real-world setting,” Paul Cockrum, PharmD, director of American Oncology HEOR at Ipsen Pharma, wrote with coauthors in the analysis.¹ “Analysis adjusting for baseline characteristics are warranted and will provide further insights for the comparative efficacy of the 2 regimens.”

The real-world analysis used de-identified patient-level, longitudinal data from the Flatiron Electronic Health Record between January 1, 2014, and February 29, 2024, to construct the 3 cohorts for the study. Of the patients identified with confirmed diagnoses of metastatic PDAC on or after January 1, 2014, 3271 were adult patients treated with first-line FOLFIRINOX, encompassing the all-comer cohort of the analysis. Additionally, a second trial-aligned cohort included members of the all-comer cohort who met the NAPOLI 3 trial eligibility criteria (n = 219).

A third trial-aligned cohort included a subgroup of patients in the second cohort who were treated with a modified FOLFIRINOX regimen (n = 154). Modified FOLFIRINOX in the third cohort was defined as receiving an initial dose of 150 mg/m² or fewer of irinotecan or an initial cumulative dose of 2720 mg/m² or fewer of 5-FU during the first cycle.

The median age on the index date of the trial aligned cohort was 65.0 years (IQR, 59.0-71.0) compared to 64.0 years (IQR, 58.0-70.0) across all-comers and 65.5 years (IQR, 60.0-72.0) in the modified FOLFIRNIOX cohort. Furthermore, male patients accounted for 54.3%, 57.9%, and 55.8% of each cohort; 66.7%, 64.8%, and 64.9% of respective cohorts were White; and the median time from metastatic diagnosis to index date was 3.0 weeks (IQR, 2.0-4.6) in the trial-aligned cohort, 3.0 weeks (IQR, 1.9-4.7) in the all-comers cohort, and 3.0 weeks (IQR, 2.0-4.4) in the modified FOLFIRINOX cohort.

All patients in the trial-aligned and modified FOLFIRNOX cohorts, as well as 82.9% of the all-comer cohort, had a known ECOG performance status. Additionally, 53.0% of the trial-aligned cohort, 34.7% of all-comers, and 50.0% of the modified FOLFIRNOX cohort had an ECOG performance status of 0. Data showed that 7.8%, 11.3%, and 9.7% of the respective cohorts were previously treated with surgery and 10.5%, 13.8%, and 12.3%, respectively, were treated with prior chemotherapy.

Phase 3 NAPOLI 3 Trial Study Design

The phase 3 NAPOLI 3 trial enrolled treatment-naïve patients with metastatic PDAC to receive either NALIRIFOX or nab-paclitaxel and gemcitabine.² Patients in the NALIRIFOX arm received 50 mg/m²of liposomal irinotecan, 60 mg/m²of oxaliplatin, 400 mg/m² of leucovorin, and 2400 mg/m² of fluorouracil sequentially as a continuous intravenous infusion over 46 hours on days 1 and 15 of a 28-day cycle. Those in the standard-of-care (SOC) cohort received 125 mg/m² of nab-paclitaxel and 1000 mg/m² of gemcitabine intravenously on days 1, 8, and 15 of a 28-day cycle.

In the NALIRIFOX arm, the median patient age was 64.0 years (range, 20-85), most patients were male (53%), and most were White (82%). Most patients on trial had an ECOG performance status of 1 (58%), 3 or more metastatic sites (39%), liver metastases (80%), and a baseline CA 19-9 of 37 U/mL or higher (84%). Additionally, 6% of patients had previous anti-cancer surgery, including 5% having a prior surgical procedure, 4% having prior chemotherapy, and 3% having prior radiotherapy.

References

1. Cockrum P, Chang R, Yu L, et al. Overall survival (OS) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line (1L) FOLFIRINOX (FFX): bridging the gap between the NAPOLI 3 trial and real-world practice. J Clin Oncol. 2025;43(suppl 4):690. doi:10.1200/JCO.2025.43.4_suppl.690
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