Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours
Maximilian J Mair1,2, Rupert Bartsch1, Emilie Le Rhun3,4
1Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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.
Insights
Antibody-drug conjugates show promise for brain tumors, with some showing intracranial activity. Further research is needed to optimize their delivery and efficacy for brain metastases and gliomas.
Area of Science:
- Oncology
- Pharmacology
- Neuroscience
Background:
- Antibody-drug conjugates (ADCs) are emerging targeted cancer therapeutics.
- Primary and secondary brain tumors have high mortality rates, requiring new treatments.
- Drug delivery to brain tumors is often limited by the blood-brain barrier.
Purpose of the Study:
- To review the central nervous system activity of ADCs in primary and secondary brain tumors.
- To discuss the clinical implications of ADC efficacy in brain tumors.
- To explore factors influencing ADC intracranial activity and optimize clinical trial design.
Main Methods:
- Review of clinical trial data on ADCs for brain tumors.
- Analysis of studies involving HER2-targeted ADCs (trastuzumab deruxtecan) and EGFR-targeted ADCs (depatuxizumab mafodotin).
- Exploration of pharmacological determinants of central nervous system activity.
Main Results:
- Trastuzumab deruxtecan demonstrated clinically relevant intracranial activity in HER2+ breast cancer brain metastases.
- Depatuxizumab mafodotin did not show significant overall survival benefit in EGFR-amplified glioblastoma.
- Objective radiological responses were observed in some patients despite lack of overall survival benefit.
Conclusions:
- ADCs hold potential for treating brain tumors, but efficacy varies.
- Understanding pharmacological determinants is crucial for optimizing ADC design for brain tumors.
- Careful clinical trial design is essential for advancing ADC development in gliomas and brain metastases.
