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

Abstract

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.