SynthesisFrontiers in oncology2026
NALIRIFOX versus FOLFIRINOX: reconstructed individual patient data meta-analysis of efficacy and safety in first-line treatment of unresectable or metastatic pancreatic ductal adenocarcinoma.
Synthesis in Frontiers in oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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: [URL], identifier (identifier number).
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