Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, with a 5-year overall survival rate below 10%. NALIRIFOX and FOLFIRINOX, both in full-dose and modified (mFOLFIRINOX) formulations, are guideline-endorsed Category 1 first-line regimens for fit patients with metastatic PDAC. However, no direct head-to-head randomized trial has compared these regimens. This systematic review and reconstructed individual patient data meta-analysis represents the first comprehensive simultaneous comparison of NALIRIFOX and FOLFIRINOX/mFOLFIRINOX across efficacy and safety outcomes.
Methods
A systematic search was conducted across PubMed, Embase, Scopus, ClinicalTrials.gov, and ASCO/ESMO proceedings from January 2011 to May 2025. Eligible studies enrolled treatment-naïve adults with unresectable or metastatic PDAC receiving first-line NALIRIFOX or FOLFIRINOX. Individual patient-level time-to-event data for overall survival (OS) and progression-free survival (PFS) were reconstructed from published Kaplan-Meier curves and pooled across studies. Treatment effects were estimated using mixed-effects Cox regression models accounting for between-study variability. Grade ≥3 adverse events were pooled using a random-effects model.
Results
Nine studies encompassing 2,733 patients were included in the primary OS analysis. Of these, 1,138 (42%) received FOLFIRINOX, 1,180 (43%) received mFOLFIRINOX, and 415 (15%) received NALIRIFOX. Six studies (n = 1,028 patients) reported PFS and were included in that analysis. The overall median OS (mOS) across all groups was 12.38 months (95% CI: 12.06–12.85). By regimen: mOS was 10.98 months (95% CI: 10.43–11.53) for FOLFIRINOX, 14.09 months (95% CI: 13.52–15.02) for mFOLFIRINOX, and 11.81 months (95% CI: 10.42–12.52) for NALIRIFOX. When FOLFIRINOX and mFOLFIRINOX were pooled, the combined group achieved a mOS of 12.59 months (95% CI: 12.21–13.27), which showed no statistically significant difference compared with NALIRIFOX (HR 1.13, 95% CI: 0.71 –1.81; p = 0.6). Moreover, no statistically significant difference was found between NALIRIFOX and full-dose FOLFIRINOX alone (HR = 1.09, 95% CI: 0.66 –1.79; p = 0.73). The overall mPFS was 7.66 months (95% CI: 7.30–8.21). By regimen: mPFS was 8.24 months (95% CI: 7.55–9.35) for FOLFIRINOX, 6.64 months (95% CI: 5.78–7.74) for mFOLFIRINOX, and 7.49 months (95% CI: 7.13–8.78) for NALIRIFOX; the pooled FOLFIRINOX/mFOLFIRINOX group achieved a mPFS of 7.71 months (95% CI: 7.23–8.41). Safety analysis confirmed distinct toxicity profiles: FOLFIRINOX carried a higher burden of grade 3/4 hematologic toxicity (neutropenia up to 45–53%; thrombocytopenia 11.8%), while NALIRIFOX was associated with lower hematologic toxicity but substantially higher grade 3/4 diarrhea (~20.3%) and hypokalemia (15.1%).
Conclusion
No statistically significant differences in OS or PFS were observed between NALIRIFOX and FOLFIRINOX. The numerically higher OS observed in the pooled FOLFIRINOX/mFOLFIRINOX group was largely driven by the mFOLFIRINOX subgroup. NALIRIFOX’s lower hematologic toxicity may reduce downstream resource utilization. Prospective head-to-head trials and biomarker-driven studies are needed.
Systematic review registration
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