Introduction: The study objective was to determine the incidence and characteristics of drug‐induced interstitial lung disease (ILD) associated with an orally available small‐molecule tyrosine kinase inhibitor, crizotinib, in a real‐world clinical setting. Methods: Post‐marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase‐positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists. Results: The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema‐like shadows with or without diffuse alveolar damage pattern were observed in crizotinib‐associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2–4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib‐induced ILD. Conclusions: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.

中文翻译：

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日本ALK阳性NSCLC患者克唑替尼治疗后间质性肺病的发生及其危险因素

介绍：该研究的目的是在真实世界的临床环境中确定与口服小分子酪氨酸激酶抑制剂克唑替尼相关的药物诱导的间质性肺病 (ILD) 的发病率和特征。方法：在日本进行了上市后监测，以获取有关克唑替尼的安全性和有效性的信息。目标患者包括在 2012 年 5 月至 2014 年 12 月的入组期间接受克唑替尼治疗的所有间变性淋巴瘤激酶阳性 NSCLC 患者。观察期为 52 周。由五名医学专家组成的 ILD 独立审查委员会对 ILD 发病率进行了专家分析。结果：安全性分析集包括 2028 名患者，超过一半的患者 (56.4%) 为非吸烟者。与克唑替尼治疗相关的 ILD 发生率为 5.77%；3.45% 的患者表现为 3 级或更高。在克唑替尼相关的 ILD 中观察到有或没有弥漫性肺泡损伤模式的肺水肿样阴影（发生率：0.39%），但无法确定与预后的因果关系。41.9% 的患者在开始使用克唑替尼后 4 周内发生 ILD，69.2% 的患者在 8 周内发生 ILD。年龄 55 岁或以上、东部肿瘤协作组体能状态 2-4、吸烟史、既往或伴随 ILD 以及合并胸腔积液被统计确定为克唑替尼诱导的 ILD 的重要危险因素。结论：对于具有上述危险因素的NSCLC患者，应谨慎监测ILD的发生，应用克唑替尼治疗。