研究动态
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了解抗体药物偶联物在原发性和继发性脑肿瘤中的活动。

Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours.

发表日期:2023 Apr 21
作者: Maximilian J Mair, Rupert Bartsch, Emilie Le Rhun, Anna S Berghoff, Priscilla K Brastianos, Javier Cortes, Hui K Gan, Nancy U Lin, Andrew B Lassman, Patrick Y Wen, Michael Weller, Martin van den Bent, Matthias Preusser
来源: Nature Reviews Clinical Oncology

摘要:

抗体药物联合物(ADC)是一类通过化学连接剂将单克隆抗体与细胞毒性荷载结合的靶向癌症治疗药物。该类药物已被批准用于治疗多种癌症类型,并正在进行新构建的广泛临床研究。原发性和继发性脑肿瘤与高死亡率和发病率相关,需要新的治疗方法。脑肿瘤的药物治疗可能受制于血脑或血肿瘤屏障的限制,尽管HER2靶向ADC曲妥珠单抗德昔汀对来自HER2 +乳腺癌的脑转移患者产生明显的颅内活性的II期研究数据。然而,靶向野生型EGFR和EGFR变异体III的ADC—去帕赛珠单抗甲醇钠,在II和III期试验中未能为新诊断或复发的EGFR扩增的胶质母细胞瘤患者提供明确的总生存益处,尽管某些患者有客观的影像学反应。在本综述中,我们总结了ADC在涉及原发性和继发性脑肿瘤患者的试验中的中枢神经系统活性可用数据,并讨论了其临床意义。此外,我们还探讨了颅内活性的药理学决定因素,并讨论了促进ADC用于胶质母细胞瘤和脑转移瘤治疗的临床试验的最佳设计。©2023 Springer Nature Limited。
Antibody-drug conjugates (ADCs), a class of targeted cancer therapeutics combining monoclonal antibodies with a cytotoxic payload via a chemical linker, have already been approved for the treatment of several cancer types, with extensive clinical development of novel constructs ongoing. Primary and secondary brain tumours are associated with high mortality and morbidity, necessitating novel treatment approaches. Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood-brain or blood-tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2+ breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.© 2023. Springer Nature Limited.