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

Nature Reviews Clinical Oncology volume 20, pages 372–389 (2023)Cite this article

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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.

Key points

  • Antibody–drug conjugates (ADCs) have shown promising clinical activity across several different solid tumour entities; however, data on the intracranial efficacy of these agents are scarce, especially in patients with active brain metastases.

  • Data from phase II trials suggest that the HER2-targeted ADC trastuzumab deruxtecan has substantial central nervous system activity in patients with breast cancer brain metastases.

  • By contrast, the EGFR-targeted ADC depatuxizumab mafodotin failed to produce an overall survival benefit in patients with glioblastoma.

  • Pharmacological determinants of the intracranial activity of ADCs include the linker design, payload used, and the drug-to-antibody ratio and its heterogeneity in the ADC formulation.

  • Dedicated, adequately powered clinical trials including rational end points of intracranial response are warranted to evaluate the efficacy of ADCs in patients with primary and secondary brain tumours.

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Fig. 1: Parameters influencing central nervous system delivery and activity of antibody–drug conjugates.

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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.

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Authors and Affiliations

  1. Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria

    Maximilian J. Mair, Rupert Bartsch, Anna S. Berghoff & Matthias Preusser

  2. Christian Doppler Laboratory for Personalized Immunotherapy, Medical University of Vienna, Vienna, Austria

    Maximilian J. Mair, Anna S. Berghoff & Matthias Preusser

  3. Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland

    Emilie Le Rhun

  4. Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland

    Emilie Le Rhun & Michael Weller

  5. Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Priscilla K. Brastianos

  6. Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Priscilla K. Brastianos

  7. International Breast Cancer Center (IBCC), Pangaea Oncology, Quirónsalud Group, Madrid and Barcelona, Spain

    Javier Cortes

  8. Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain

    Javier Cortes

  9. Medical Scientia Innovation Research (MEDSIR), Barcelona, Spain

    Javier Cortes

  10. Cancer Therapies and Biology Group, Centre of Research Excellence in Brain Tumours, Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital, Heidelberg, VIC, Australia

    Hui K. Gan

  11. La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia

    Hui K. Gan

  12. Department of Medicine, University of Melbourne, Heidelberg, VIC, Australia

    Hui K. Gan

  13. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Nancy U. Lin

  14. Division of Neuro-Oncology, Department of Neurology, Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Hospital, New York, NY, USA

    Andrew B. Lassman

  15. Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Patrick Y. Wen

  16. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Patrick Y. Wen

  17. The Brain Tumour Center, Erasmus Medical Center Cancer Institute, Rotterdam, Netherlands

    Martin van den Bent

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Contributions

M.J.M. and M.P. wrote the initial draft of the manuscript. All authors provided substantial intellectual input and reviewed and/or edited the manuscript prior to submission.

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Correspondence to Matthias Preusser.

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Competing interests

M.J.M. has received travel support from Pierre Fabre. E.LeR. has received grant/research support from Bristol Myers Squibb; and honoraria for lectures or advisory board participation from Adastra, Bayer, Janssen, Leo Pharma, Pierre Fabre and Seattle Genetics. A.S.B. has received research support from Daiichi Sankyo and Roche; honoraria for lectures, consultation or advisory board participation from Bristol Myers Squibb, Daiichi Sankyo, Merck and Roche; and travel support from AbbVie, Amgen and Roche. P.K.B. has consulted for Advice Connect Inspire, Angiochem, Axiom, Dantari, ElevateBio, Genentech/Roche, Lilly, MPM Capital, Pfizer, SK Life Sciences and Tesaro; has received institutional grant/research support (to Massachusetts General Hospital) from Bristol Myers Squibb, Lilly, Merck and Mirati; and has received honoraria from Genentech/Roche, Lilly, Merck and Pfizer (all outside the scope of this work). N.U.L. has received non-financial support from Seagen for manuscript preparation during the conduct of research studies; grants from AstraZeneca, Genentech, Merck, Olema Pharmaceuticals, Pfizer, Seagen and Zion Pharmaceuticals outside the submitted work; personal fees from Affinia Therapeutics, Aleta BioPharma, AstraZeneca, Daiichi Sankyo, Denali Therapeutics, Olema Pharmaceuticals, Pfizer, Prelude Therapeutics, Puma, Seagen and Voyager Therapeutics outside the submitted work; consulting fees from Affinia Therapeutics, Aleta BioTherapeutics, Artera, AstraZeneca, Daiichi Sankyo, Denali Therapeutics, Olema Oncology, Pfizer, Prelude Therapeutics, Seagen and Voyager Therapeutics; and royalties from UpToDate outside the submitted work. A.B.L. has received within the past 5 years travel, publication, other in-kind support, honoraria for consulting or advisory board participation and institutional research funding from Abbott and/or AbbVie, and in the past year has received travel, publication or other in-kind support from Chimerix, Karyopharm, Norwest Biotherapeutics, Pfizer, QED and VBI Vaccines; honoraria for consulting or advisory board participation from Affinia Therapeutics, Bioclinica (as an expert, blinded, independent reviewer of de-identified clinical data for a Bristol Myers Squibb-sponsored trial), Chimerix, Clinical Education Alliance, Leal Therapeutics, Novocure, Orbus and Sapience; and institutional research funding from AbbVie, Aeterna Zentaris, Bayer, Beigene, Bristol Myers Squibb, Cadmon, Chimerix, DelMar, Genentech/Roche, Kadmon, Karyopharm, Kazia, Keryx, Millennium, NextSource, Orbus, Pfizer, QED, Semus, Servier and VBI Vaccines. P.Y.W. has received honoraria for consulting or advisory board participation from AstraZeneca, Bayer, Black Diamond Therapeutics, Cellularity, Chimerix, Day One Biopharmaceuticals, Kazia, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience Therapeutics, Servier, Tocagen, Vascular Biogenics and VBI Vaccines; and research funding from Agios, AstraZeneca, Bayer, Beigene, Celgene, Chimerix, Karyopharm Therapeutics, Kazia, MedicicNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Puma Biotechnology, Vacular Biogenics and VBI Vaccines. M.W. has received research grants from Quercis and Versameb; and honoraria for lectures or advisory board participation or consulting from Bayer, Medac, Merck (EMD), Novartis, Orbus and Philogen. M.P. has received honoraria for lectures, consultation or advisory board participation from AbbVie, AstraZeneca, Bayer, BMJ Journals, Bristol Myers Squibb, CMC Contrast, Daiichi Sankyo, Gerson Lehrman Group, GlaxoSmithKline, Lilly, Medahead, MedMedia, Merck Sharp & Dohme, Mundipharma, Novartis, Roche, Sanofi and Tocagen; and institutional research support from AbbVie, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Merck Sharp & Dohme, Novocure and Roche. R.B., J.C., H.K.G. and M.v.d.B. declare no competing interests.

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Nature Reviews Clinical Oncology thanks P. Kumthekar, T. Johns and M. Valiente for their contribution to the peer review of this work.

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Common Terminology Criteria for Adverse Events (CTCAE): https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm

EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search

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Mair, M.J., Bartsch, R., Le Rhun, E. et al. Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours. Nat Rev Clin Oncol 20, 372–389 (2023). https://doi.org/10.1038/s41571-023-00756-z

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