ALK阻害薬の徐脈の副作用

論文No2929

ALK inhibitor-induced bradycardia: A systematic-review and meta-analysis
Filipe Cirne,Shijie Zhou,Coralea Kappel,...Peter M. Ellis,Stephanie Sanger,Darryl P. Leong
LUNG CANCER, VOLUME 161, P9-17, NOVEMBER 01, 2021

＜背景＞

ALK阻害薬は進行ALK陽性NSCLCの治療に革命を起こし、無増悪生存期間(PFS)は延長した。

徐脈はALK阻害薬の副作用である。

我々は進行NSCLC患者においてALK阻害薬関連の徐脈のリスクを検討した。

＜方法＞

MEDLINE, EMBASE, Cochrane Central Register od Controlled Trial, National clinical trial registry,

Web of Sciense Core Collectionのシステマティック検索を行った。
ALK阻害薬が他のALK阻害薬や標準化学療法と比較されたランダム化コントロール試験すべてを検討した。

メタ解析を行い、固定効果モデルを使用して徐脈、ふらつきの累積頻度を評価した。

＜結果＞

1737名のALK阻害薬投与患者の徐脈の累積頻度は8%で平均フォローアップは1.26年であった。

クリゾチニブは標準化学療法よりも徐脈の頻度が高かった（相対リスク, RR 24.68, 95% CI 7.11–85.)。

しかしクリゾチニブとアレクチニブとに差はなかった (RR 1.12, 95% CI 0.79–1.59)。
次世代ALK阻害薬のアレクチニブ、ブリガチニブ、ロルラチニブをあわせた検討では

クリゾチニブと同等の頻度であった (RR 0.77, 95% CI 0.57–1.04）。
すべてのALK阻害薬（全体として）は標準化学療法よりもふらつき（徐脈の症状の可能性）が多かった(RR 1.88, 95% CI 1.44–2.44)。

＜感想＞

ALK阻害薬のうちクリゾチニブは徐脈のリスクが標準化学療法よりも高かったようですが、

他のALK阻害薬との間で有意差はなかったようです。

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.