NALIRIFOX shows no significant difference in overall survival compared to FOLFIRINOX in pancreatic cancerNALIRIFOX Shows Similar Survival Rates to FOLFIRINOX for Pancreatic Cancer

BackgroundPancreatic 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.MethodsA 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.ResultsNine 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%).ConclusionNo 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)