Stefanovski Dimitar, Manevski Damjan, Ribnikar Domen, Šeruga Boštjan
Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška Cesta 2, 1000 Ljubljana, Slovenia.
Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, 1000 Ljubljana, Slovenia.
Cancers (Basel). 2025 Feb 8;17(4):584. doi: 10.3390/cancers17040584.
New safety concerns about targeted anticancer agents (TAAs) often emerge in the first few years after their initial regulatory approval. Our aim was to determine whether new serious and potentially fatal adverse drug reactions (ADRs) continue to emerge in the updated drug labels of TAAs several years after their initial regulatory approval and whether their emergence can be predicted. The updated drug labels of TAAs approved by the U.S. Food and Drug Administration before July 2013 were analyzed. Serious and potentially fatal ADRs were identified in the Warnings & Precautions (WPs) and Boxed Warnings (BWs) sections of the updated drug labels. Generalized linear mixed models were used to examine the associations between the number of adverse drug reactions and time, drug type (small molecules vs. monoclonal antibodies), and the availability of companion diagnostics for biomarkers. Among 37 eligible TAAs, 25 (68%) were small molecules and 11 (30%) had available companion diagnostics for the biomarkers. Time was a significant predictor of new WPs ( ˂ 0.001) and BWs ( = 0.008). The updated drug labels of the small molecules received significantly more new WPs ( = 0.042) as compared to monoclonal antibodies. The availability of the companion diagnostics for the biomarkers did not have an impact on the emergence of new ADRs. New serious ADRs of TAAs continue to emerge in updated drug labels several years after their initial regulatory approval. Oncologists, regulators, and payers should be aware of the changing risk-benefit ratios of approved TAAs.
针对抗癌靶向药物（TAAs）的新安全问题通常在其首次获得监管批准后的头几年出现。我们的目的是确定在TAAs首次获得监管批准数年之后，其更新后的药品标签中是否会继续出现新的严重及潜在致命药物不良反应（ADR），以及这些不良反应的出现是否可以预测。我们分析了2013年7月之前美国食品药品监督管理局批准的TAAs更新后的药品标签。在更新后的药品标签的“警告与注意事项”（WPs）和“黑框警告”（BWs）部分中识别出严重及潜在致命的ADR。使用广义线性混合模型来检验药物不良反应数量与时间、药物类型（小分子药物与单克隆抗体）以及生物标志物伴随诊断的可用性之间的关联。在37种符合条件的TAAs中，25种（68%）为小分子药物，11种（30%）具有针对生物标志物的可用伴随诊断。时间是新WPs（˂0.001）和BWs（=0.008）的显著预测因素。与单克隆抗体相比，小分子药物的更新药品标签获得了显著更多的新WPs（=0.042）。生物标志物伴随诊断的可用性对新ADR的出现没有影响。TAAs的新严重ADR在其首次获得监管批准数年之后的更新药品标签中继续出现。肿瘤学家、监管机构和支付方应了解已批准TAAs不断变化的风险效益比。
