Supplementary file 1_NALIRIFOX versus FOLFIRINOX: reconstructed individual patient data meta-analysis of efficacy and safety in first-line treatment of unresectable or metastatic pancreatic ductal adenocarcinoma.docx

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.</p>Results<p>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%).</p>Conclusion<p>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.</p>Systematic review registration<p>[URL], identifier (identifier number)</p>