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The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>All ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 3,048 Italian reports, most of ADRs were related to ERL (<jats:italic>n<\/jats:italic> = 1,448), followed by AFT (<jats:italic>n<\/jats:italic> = 435) and GEF (<jats:italic>n<\/jats:italic> = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group &amp;gt;65 years (53.0%). A higher number of cases were related to skin disorders (<jats:italic>n<\/jats:italic> = 1,766; 57.9%), followed by gastrointestinal disorders (<jats:italic>n<\/jats:italic> = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (<jats:italic>n<\/jats:italic> = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (<jats:italic>n<\/jats:italic> = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.1005626","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T06:45:05Z","timestamp":1669185905000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database"],"prefix":"10.3389","volume":"12","author":[{"given":"Maria Antonietta","family":"Barbieri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuela 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