{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:11:38Z","timestamp":1790683898612,"version":"4.1.0"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The cultivating scientific research project of the Second Hospital of Dalian Medical University","award":["YJ20250033"],"award-info":[{"award-number":["YJ20250033"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Entrectinib is effective for ROS1-positive non-small cell lung cancer (NSCLC), but its postmarketing safety profile remains incompletely characterized outside clinical trials. We conducted a dual-database pharmacovigilance study to characterize real-world reporting patterns, identify cross-database replicated adverse event signals, explore age- and sex-related reporting heterogeneity, and evaluate time-to-onset patterns.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Reports were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS; 2020Q1\u20132025Q4; 520 patients; 1,573 preferred-term [PT] events) and the Japanese Adverse Drug Event Report database (JADER; 2020Q1\u20132025Q3; 254 patients; 393 PT events). Molecular fusion status was not available for verification. Four disproportionality methods were applied, with reporting odds ratio (ROR) as the primary signal criterion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At the system organ class level, shared positive signals involved nervous system disorders (FAERS\/JADER ROR: 4.48\/4.76), cardiac disorders (3.20\/5.43), and renal and urinary disorders (2.04\/3.92). At the PT level, 23 signals were detected in both databases, whereas 58 PTs were unique to FAERS and 8 to JADER. Representative shared PT signals included dizziness (12.94\/14.33), taste disorder (38.03\/13.28), renal impairment (6.89\/8.18), blood creatinine increased (8.31\/24.99), cardiac failure (7.57\/8.90), cognitive disorder (18.04\/78.29), ataxia (51.73\/351.45), syncope (8.87\/89.45), myocarditis (3.47\/5.91), electrocardiogram QT prolonged (4.01\/5.35), and hyperuricaemia (7.36\/59.63). Subgroup analyses suggested exploratory age- and sex-related reporting heterogeneity, including relatively more renal and mobility-related reports in older patients and female predominance for ataxia in FAERS. In the FAERS-based time-to-onset analysis, 203 of 520 reports (39.0%) had valid onset data. The median time to onset was 13 days, 70.94% of evaluable reports had onset dates within 30 days, and Weibull analysis suggested an early-failure pattern.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Entrectinib-associated reports in NSCLC showed reproducible neurologic, cardiac, renal, and laboratory-related disproportional reporting signals across FAERS and JADER. These findings may help prioritize early safety monitoring but should be interpreted as hypothesis-generating signals rather than evidence of incidence or causality.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0358331","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:36:11Z","timestamp":1789493771000},"page":"e0358331","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Safety profile of entrectinib in NSCLC: Multi-source pharmacovigilance analysis using FAERS and JADER"],"prefix":"10.1371","volume":"21","author":[{"given":"JiaLe","family":"Yang","sequence":"first","affiliation":[{"name":"The Second Hospital of Dalian Medical University","place":["Dalian, China"],"department":["Department of Thoracic Surgery"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiaWen","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Hospital of Dalian Medical University","place":["Dalian, China"],"department":["Department of Thoracic Surgery"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuanBo","family":"Zhao","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HeChen","family":"Li","sequence":"additional","affiliation":[{"name":"Dalian Medical University","place":["Dalian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4723-7825","authenticated-orcid":true,"given":"Ge","family":"Sun","sequence":"additional","affiliation":[{"name":"The Second Hospital of Dalian Medical University","place":["Dalian, China"],"department":["Department of Thoracic Surgery"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"1","key":"pone.0358331.ref001","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"RL Siegel","year":"2023","journal-title":"CA Cancer J Clin"},{"issue":"8","key":"pone.0358331.ref002","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1200\/JCO.2011.35.6345","article-title":"ROS1 rearrangements define a unique molecular class of lung cancers","volume":"30","author":"K Bergethon","year":"2012","journal-title":"J Clin Oncol"},{"issue":"6","key":"pone.0358331.ref003","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s40265-021-01503-3","article-title":"Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC","volume":"81","author":"JE Frampton","year":"2021","journal-title":"Drugs"},{"issue":"2","key":"pone.0358331.ref004","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S1470-2045(19)30690-4","article-title":"Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials","volume":"21","author":"A Drilon","year":"2020","journal-title":"Lancet Oncol"},{"key":"pone.0358331.ref005","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1471-2288-14-17","article-title":"Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases","volume":"14","author":"F Leroy","year":"2014","journal-title":"BMC Med Res Methodol"},{"key":"pone.0358331.ref006","doi-asserted-by":"crossref","first-page":"108478","DOI":"10.1016\/j.lungcan.2025.108478","article-title":"Real-world safety and effectiveness of entrectinib in Japanese patients with ROS1 gene fusion-positive, unresectable, advanced\/recurrent non-small cell lung cancer: Post-marketing surveillance","volume":"203","author":"T Seto","year":"2025","journal-title":"Lung Cancer"},{"issue":"6","key":"pone.0358331.ref007","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/clpt.2013.24","article-title":"Performance of pharmacovigilance signal-detection algorithms for the FDA adverse event reporting system","volume":"93","author":"R Harpaz","year":"2013","journal-title":"Clin Pharmacol Ther"},{"issue":"2","key":"pone.0358331.ref008","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/pds.4944","article-title":"Quality evaluation of the Japanese Adverse Drug Event Report database (JADER)","volume":"29","author":"M Tsuchiya","year":"2020","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"6","key":"pone.0358331.ref009","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s40264-015-0289-5","article-title":"Comparison of statistical signal detection methods within and across spontaneous reporting databases","volume":"38","author":"G Candore","year":"2015","journal-title":"Drug Saf"},{"issue":"23","key":"pone.0358331.ref010","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1056\/NEJMsb1609216","article-title":"Real-World Evidence - 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