First-Line FOLFIRINOX Fails to Improve OS vs First-Line NALIRIFOX in Metastatic PDAC

A real-world retrospective cohort study showed that the median overall survival (OS) with frontline FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) was numerically lower than the median OS that was previously shown with frontline NALIRIFOX (liposomal irinotecan, 5-fluorouracil [5-FU], leucovorin, and oxaliplatin) in this population in the phase 3 NAPOLI 3 trial (NCT04083235).1

The real-world findings, which were presented at the 2025 ASCO Gastrointestinal Cancers Symposium, demonstrated that treatment with FOLFIRINOX in a trial-aligned cohort of patients who met the eligibility criteria for the NAPOLI 3 trial (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 in NAPOLI 3. Furthermore, the median OS was 9.0 months (95% CI, 8.5-9.3) for all-comer patients with mPDAC treated with first-line FOLFIRINOX between January 1, 2014, and February 29, 2024 (n = 3271). An additional trial-aligned cohort of patients treated with modified FOLFIRINOX (mFOLFIRINOX; n = 154) 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 [mFOLFIRINOX], in the real-world setting,” Paul Cockrum, PharmD, director of American Oncology HEOR at Ipsen Pharma, wrote with coauthors in the study.1 “Analyses 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 collected between January 1, 2014, and February 29, 2024, to construct the 3 cohorts for the study. All adult patients identified with confirmed diagnoses of mPDAC on or after January 1, 2014, who were treated with first-line FOLFIRINOX encompassed the all-comer cohort of the analysis. A second, trial-aligned cohort included members of the all-comer cohort who met the NAPOLI 3 trial eligibility criteria.

A third cohort included a subgroup of patients in the second cohort who were treated with mFOLFIRINOX. mFOLFIRINOX in the third cohort was defined as an initial dose of 150 mg/m2 or lower of irinotecan or an initial cumulative dose of 2720 mg/m2 or lower of 5-FU during the first cycle.

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

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

Phase 3 NAPOLI 3 Trial Design

The phase 3 NAPOLI 3 trial enrolled treatment-naive patients with mPDAC to receive either NALIRIFOX or nab-paclitaxel (Abraxane) plus 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 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 patients 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 level of 37 U/mL or higher (84%). Additionally, 6% of patients had undergone any previous anticancer therapy, including a surgical procedure (5%), chemotherapy (4%), and radiotherapy (3%).

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