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

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

doi:10.1038/s41571-023-00756-z

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

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^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Review article › Academic › peer-review

44 Citations (Scopus)

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.

Original language	English
Pages (from-to)	372-389
Number of pages	18
Journal	Nature Reviews Clinical Oncology
Volume	20
Issue number	6
DOIs	https://doi.org/10.1038/s41571-023-00756-z
Publication status	Published - Jun 2023

Bibliographical note

Acknowledgements:
M.J.M, A.S.B and M.P. gratefully acknowledge financial support from the Austrian Federal Ministry for Digital and Economic Affairs, the Austrian National Foundation for Research, Technology and Development, and the Christian Doppler Research Association. The work of A.B.L. is supported in part, outside the submitted work, by The William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at New York-Presbyterian Hospital, The Michael Weiner Glioblastoma Research Into Treatment Fund, and US National Institutes of Health (NIH)/National Cancer Institute (NCI) grants P30CA013696 and UG1CA189960. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH/NCI.

Publisher Copyright:
© 2023, Springer Nature Limited.

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Mair, M. J., Bartsch, R., Le Rhun, E., Berghoff, A. S., Brastianos, P. K., Cortes, J., Gan, H. K., Lin, N. U., Lassman, A. B., Wen, P. Y., Weller, M., van den Bent, M., & Preusser, M. (2023). Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours. Nature Reviews Clinical Oncology, 20(6), 372-389. https://doi.org/10.1038/s41571-023-00756-z

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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.",

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AU - Wen, Patrick Y.

AU - Weller, Michael

AU - van den Bent, Martin

AU - Preusser, Matthias

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N2 - 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.

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

Abstract

Bibliographical note

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