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This study aimed to directly compare the relative risk (RR) of hepatotoxicity between new-generation (afatinib, osimertinib, dacomitinib) and first-generation (gefitinib, erlotinib) EGFR-TKIs in non-small-cell lung cancer (NSCLC) and to evaluate their overall risk-benefit profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PubMed, Embase, Cochrane library databases and clinicaltrials.gov were searched for trials up to September 2025. A study protocol was registered in PROSPERO: CRD42023457906. Among the 5371 records identified, 6 studies finally fulfilled the established criteria. Data extracted for each study included study characteristics, baseline patient information, interventions and data on all-grades alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) elevation, overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). RR, hazard ratio (HR) and 95% confidence interval (CI) were calculated using the inverse variance method.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Six trials involving 2528 patients were analyzed. Decreased risks of hepatotoxicity due to the elevation of AST and ALT were observed for each new-generation EGFR-TKI. The pooled RRs of all-grades ALT, AST and TB elevation were 0.36 (95% CI 0.24\u20130.52,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), 0.44 (95% CI 0.36\u20130.54,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001) and 0.83 (95% CI 0.50\u20131.39,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.48), respectively. New-generation TKIs did achieved benefit in PFS (HR 0.65, 95% CI 0.50\u20130.83,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and ORR (RR 1.14, 95% CI 1.00-1.29,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.04). The OS of patients with new-generation TKI treatment was extended (afatinib, HR 0.73, 95% CI 0.58\u20130.92,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.008 and osimertinib, HR 0.71, 95% CI 0.53\u20130.95,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.02), except dacomitinib (HR 0.97, 95% CI 0.72\u20131.29,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.81).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>New-generation EGFR-TKIs (afatinib, osimertinib, and dacomitinib) demonstrate a superior efficacy and safety profile, with a significantly lower risk of hepatotoxicity, compared to gefitinib and erlotinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12885-025-15330-2","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T22:58:32Z","timestamp":1767049112000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatotoxicity and efficacy associated with first- and new-generation EGFR-TKIs in patients with NSCLC: a systematic review and meta-analysis"],"prefix":"10.1186","volume":"25","author":[{"given":"Zhe","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jipeng","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanlin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengrui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"issue":"3","key":"15330_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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