{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:05:29Z","timestamp":1789707929793,"version":"4.0.1"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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-na\u00efve 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 \u22653 adverse events were pooled using a random-effects model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats: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\u201312.85). By regimen: mOS was 10.98 months (95% CI: 10.43\u201311.53) for FOLFIRINOX, 14.09 months (95% CI: 13.52\u201315.02) for mFOLFIRINOX, and 11.81 months (95% CI: 10.42\u201312.52) for NALIRIFOX. When FOLFIRINOX and mFOLFIRINOX were pooled, the combined group achieved a mOS of 12.59 months (95% CI: 12.21\u201313.27), which showed no statistically significant difference compared with NALIRIFOX (HR 1.13, 95% CI: 0.71 \u20131.81; p = 0.6). Moreover, no statistically significant difference was found between NALIRIFOX and full-dose FOLFIRINOX alone (HR\u00a0=\u00a01.09, 95% CI: 0.66 \u20131.79; p = 0.73). The overall mPFS was 7.66 months (95% CI: 7.30\u20138.21). By regimen: mPFS was 8.24 months (95% CI: 7.55\u20139.35) for FOLFIRINOX, 6.64 months (95% CI: 5.78\u20137.74) for mFOLFIRINOX, and 7.49 months (95% CI: 7.13\u20138.78) for NALIRIFOX; the pooled FOLFIRINOX\/mFOLFIRINOX group achieved a mPFS of 7.71 months (95% CI: 7.23\u20138.41). Safety analysis confirmed distinct toxicity profiles: FOLFIRINOX carried a higher burden of grade 3\/4 hematologic toxicity (neutropenia up to 45\u201353%; thrombocytopenia 11.8%), while NALIRIFOX was associated with lower hematologic toxicity but substantially higher grade 3\/4 diarrhea (~20.3%) and hypokalemia (15.1%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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\u2019s lower hematologic toxicity may reduce downstream resource utilization. Prospective head-to-head trials and biomarker-driven studies are needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>[URL], identifier (identifier number)<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1902839","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:34:14Z","timestamp":1789706054000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["NALIRIFOX versus FOLFIRINOX: reconstructed individual patient data meta-analysis of efficacy and safety in first-line treatment of unresectable or metastatic pancreatic ductal adenocarcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Abdullah","family":"Esmail","sequence":"first","affiliation":[{"name":"Section of GI Oncology, Department of Medicine, Houston Methodist 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Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebtesam","family":"Al-Najjar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan","place":["Amman, Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saifudeen","family":"Abdelrahim","sequence":"additional","affiliation":[{"name":"Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan","place":["Amman, Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayan","family":"Khasawneh","sequence":"additional","affiliation":[{"name":"Section of GI Oncology, Department of Medicine, Houston Methodist Cancer Center","place":["Houston, TX, United 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