Introduction: Immune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype‐directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene‐driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described. Methods: Patients with advanced ALK receptor tyrosine kinase (ALK)‐driven, ROS1‐driven, or MET proto‐oncogene, receptor tyrosine kinase (MET)‐driven NSCLC treated with crizotinib, with or without preceding ICI therapy, were identified. The cumulative incidences of crizotinib‐associated grade 3 or higher increases in transaminase level (per the Common Terminology Criteria for Adverse Events, version 4.0) were compared. Results: We identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto‐oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9–72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0–64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7–11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9–5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy's law criteria. Conclusions: Sequential ICI and crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib after ICI therapy.

中文翻译：

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简报：非小细胞肺癌患者中与序贯免疫检查点抑制剂和克唑替尼治疗相关的肝毒性增加

简介：免疫检查点抑制剂 (ICI) 是晚期 NSCLC 的标准疗法。尽管基因型导向的酪氨酸激酶抑制剂代表了癌基因驱动的 NSCLC 亚群的标准治疗，但患者可能在病程中接受 ICI。尚未描述序贯 ICI 和酪氨酸激酶抑制剂治疗对肝毒性风险的影响。方法：确定了接受克唑替尼治疗的晚期 ALK 受体酪氨酸激酶 (ALK) 驱动、ROS1 驱动或 MET 原癌基因受体酪氨酸激酶 (MET) 驱动的非小细胞肺癌患者，无论是否接受 ICI 治疗。比较了与克唑替尼相关的 3 级或更高级别转氨酶水平升高的累积发生率（根据不良事件通用术语标准，4.0 版）。结果：我们确定了 453 名 NSCLC 患者的 ALK 受体酪氨酸激酶基因 (ALK)、ROS1 或 MET 原癌基因、受体酪氨酸激酶基因 (MET) 的致癌改变，并接受了克唑替尼治疗（11 名接受过 ICI 治疗，442 名未接受过 ICI 治疗） ）。在接受 ICI 继以克唑替尼治疗的 11 名患者中，5 名（累积发生率 45.5% [95% 置信区间 (CI)：14.9–72.2]）的丙氨酸转氨酶水平升高 3 或 4 级，4 名（累积发生率36.4% [95% CI: 10.0–64.2]) 的天冬氨酸转氨酶水平出现 3 或 4 级升高。相比之下，在仅接受克唑替尼治疗的 442 名患者中，34 名患者的丙氨酸转氨酶水平升高 3 或 4 级（累积发生率为 8.1% [95% CI：5.7-11.0，p < 0。0001]) 和 14 例天冬氨酸转氨酶水平升高 3 或 4 级（累积发生率为 3.4% [95% CI：1.9-5.5，p < 0.0001]）。没有 5 级转氨酶事件。序贯 ICI 和克唑替尼使用后的所有肝毒性病例都是可逆的和非致命性的，并且没有病例符合 Hy 定律标准。结论：序贯 ICI 和克唑替尼治疗与肝毒性风险显着增加相关。在 ICI 治疗后接受克唑替尼治疗的患者可能需要仔细考虑和监测肝毒性。s 法律标准。结论：序贯 ICI 和克唑替尼治疗与肝毒性风险显着增加相关。在 ICI 治疗后接受克唑替尼治疗的患者可能需要仔细考虑和监测肝毒性。s 法律标准。结论：序贯 ICI 和克唑替尼治疗与肝毒性风险显着增加相关。在 ICI 治疗后接受克唑替尼治疗的患者可能需要仔细考虑和监测肝毒性。