Introduction

Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC.

Materials and methods

We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models.

Results

The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11–85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79–1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57–1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44–2.44). Conclusion: Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.

中文翻译：

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ALK 抑制剂诱导的心动过缓：系统评价和荟萃分析

介绍

间变性淋巴瘤激酶 (ALK) 抑制剂彻底改变了晚期 ALK 阳性非小细胞肺癌 (NSCLC) 的治疗，提高了无进展生存期。心动过缓是这些药物的潜在不良反应。我们旨在确定晚期 NSCLC 患者中与 ALK 抑制剂相关的心动过缓风险。

材料和方法

我们对 MEDLINE、EMBASE、Cochrane Central Register of Controlled Trials、国家临床试验注册中心和 Web of Science 核心合集进行了系统检索。我们纳入了所有将 ALK 抑制剂与另一种 ALK 抑制剂或标准化疗进行比较的随机对照试验。使用固定效应模型进行荟萃分析以评估心动过缓和头晕的合并发病率。

结果

在 1.26 年的平均随访期间，1737 名服用 ALK 抑制剂的个体中心动过缓的合并发生率为 8%。与标准化疗相比，克唑替尼导致更多的心动过缓（相对风险，RR 24.68，95% CI 7.11-85。），而克唑替尼和艾乐替尼之间没有差异（RR 1.12，95% CI 0.79-1.59）。与克唑替尼相比，下一代 ALK 抑制剂艾乐替尼、布加替尼和劳拉替尼联合导致的心动过缓发生率相似（RR 0.77，95% CI 0.57–1.04）。与标准化疗相比，所有 ALK 抑制剂（总体而言）引起更多的头晕（作为心动过缓的潜在症状）（RR 1.88，95% CI 1.44–2.44）。结论：与标准化疗相比，用于治疗 NSCLC 的克唑替尼与更高的心动过缓风险相关。没有证据表明克唑替尼和新型 ALK 抑制剂在心动过缓风险方面存在差异。