Rashmi Shah Consultancy Ltd, Birchdale, Gerrards Cross, Buckinghamshire SL9 7JA, UK.
Drug Saf. 2013 Jun;36(6):413-26. doi: 10.1007/s40264-013-0050-x.
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, raising hopes for many patients with otherwise unresponsive tumours. While these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. Many of these toxic effects result from downstream inhibition of vascular endothelial growth factor or epidermal growth factor signalling in cells of normal organs. Many of these undesirable effects such as hypertension, hypothyroidism, skin reactions and possibly proteinuria are on-target effects. Since tyrosine kinases are widely distributed with specific functional roles in different organs, this association is not too surprising. Various studies suggest that the development of these on-target effects indicates clinically desirable and effective inhibition of the corresponding ligand-mediated receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target adverse effects compared with those who do not. Inevitably, issues arise with respect to the regulatory assessment of efficacy and risk/benefit of the TKIs as well as the clinical approach to managing patients who develop these effects. Routine subgroup analysis of efficacy data from clinical trials (patients with and without on-target toxicity) may enable more effective clinical use of TKIs since (i) discontinuing or reducing the dose of the TKI has a negative impact if the tumour is TKI-responsive; and (ii) it is usually possible to manage these undesirable on-target effects with conventional clinical approaches. Prospective studies are needed to investigate this proposition further.
酪氨酸激酶抑制剂（TKIs）彻底改变了某些类型癌症的治疗方法，给许多对其他治疗方法没有反应的肿瘤患者带来了希望。虽然这些药物通常耐受性良好，但临床应用经验突显了它们与各种器官（如心脏、肺、肝、肾、甲状腺、皮肤、凝血、胃肠道和神经系统）严重毒性作用的意外关联。这些毒性作用中的许多是由于血管内皮生长因子或表皮生长因子信号在正常器官细胞中的下游抑制所致。许多这些不良影响，如高血压、甲状腺功能减退、皮肤反应和可能的蛋白尿，都是靶向作用。由于酪氨酸激酶广泛分布，在不同器官中具有特定的功能作用，因此这种关联并不奇怪。各种研究表明，这些靶向作用的发展表明相应配体介导的受体与肿瘤发生的有效抑制具有临床意义。这反映在与未发生这些靶向不良反应的患者相比，发生这些靶向不良反应的患者亚组的疗效得到了改善。不可避免地，这就产生了关于 TKI 的疗效和风险/获益的监管评估以及管理发生这些影响的患者的临床方法的问题。对临床试验的疗效数据（有和无靶向毒性的患者）进行常规亚组分析，可能会使 TKI 的临床应用更加有效，因为 (i) 如果肿瘤对 TKI 有反应，那么停止或减少 TKI 的剂量会产生负面影响；(ii) 通常可以通过常规临床方法来管理这些不良的靶向作用。需要前瞻性研究进一步探讨这一观点。
