Tyrosine kinase inhibitors-associated interstitial lung disease used in non-small cell lung cancer: a pharmacovigilance analysis based on the FDA adverse event reporting system database

Interstitial lung disease (ILD) was a relatively common cause of drug-induced mortality. However, the safety profile of the whole TKIs induced ILD was largely unknown. The reported cases of ILD associated with TKIs were downloaded from the FDA adverse event reporting system (FAERS) database between 1 January 2004 and 30 April 2022 to detect ILD signals by disproportionality analysis. Furthermore, the fatality rate and time to onset (TTO) of various TKIs were also calculated. The median age of total 2999 reported cases was 67. The largest reported cases came from osimertinib (n = 736, 24.5%). However, gefitinib had the highest ROR of 12.47 (11.4, 13.64) and IC of 3.53 (3.23, 3.86), means the strongest association with ILD. Trametinib, vemurafenib, larotectinib, selpercatinib, and cabozantinib did not show ILD signal. The median age of dead cases was 72 (Q1:62, Q3:83), and 53.02% (n = 579) were female and 41.11% (n = 449) were male. MET group showed the highest fatality rate of 55.17% with the shortest median TTO of 21 days (Q1: 8.5, Q3: 35.5). TKIs were significantly associated with ILD. More attention should be paid to female, older, MET group with shorter TTO, as their prognosis might be worse.间质性肺病（Interstitial lung disease, ILD）是药物诱导死亡的相对常见诱因之一。然而，各类酪氨酸激酶抑制剂（Tyrosine Kinase Inhibitors, TKIs）诱发ILD的整体安全性特征仍未完全明确。本研究从2004年1月1日至2022年4月30日的美国食品药品监督管理局不良事件报告系统（FDA Adverse Event Reporting System, FAERS）数据库中下载了与TKIs相关的ILD报告病例，采用不成比例分析（disproportionality analysis）方法挖掘ILD信号。此外，本研究还计算了不同TKIs相关ILD病例的病死率及发病时间（Time to Onset, TTO）。本次纳入分析的全部2999例报告病例的中位年龄为67岁，其中报告病例数最多的为奥希替尼（osimertinib，n=736，占总报告例数的24.5%）。但吉非替尼（gefitinib）的报告比值比（Reporting Odds Ratio, ROR）最高，达12.47（95%置信区间：11.4~13.64），信息成分（Information Component, IC）为3.53（95%置信区间：3.23~3.86），提示其与ILD的关联性最强。曲美替尼（trametinib）、维莫非尼（vemurafenib）、拉罗替尼（larotectinib）、塞普替尼（selpercatinib）及卡博替尼（cabozantinib）未检出ILD信号。死亡病例的中位年龄为72岁（四分位数间距：Q1=62，Q3=83），其中女性占53.02%（n=579），男性占41.11%（n=449）。MET组（MET group）的病死率最高，达55.17%，其中位发病时间最短，仅为21天（四分位数间距：Q1=8.5，Q3=35.5）。研究结果表明，TKIs与ILD存在显著关联性。临床中应重点关注女性、老年患者以及MET组患者，此类群体发病时间较短，预后或更差。