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Antiangiogenic–immune-checkpoint inhibitor combinations: lessons from phase III clinical trials

Nature Reviews Clinical Oncology (2024)Cite this article

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Abstract

Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF–VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic–ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent–ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF–VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling.

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Fig. 1: Balance between beneficial and detrimental effects of antiangiogenic–ICI combinations.
Fig. 2: Overall survival improvement caused by antiangiogenic–ICI combinations in different cancers.

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Acknowledgements

H.-Y.K. is the recipient of grants from the National Science and Technology Council, Taiwan (R.O.C.) (111-2917-I-002-008) and the National Taiwan University Hospital. R.S.K. receives grant support from the Canadian Institutes for Health Research (CIHR). The authors are grateful to clinical colleagues, especially G. Bjarnason, (Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto), and to basic research colleagues for critical reading of the manuscript. We also thank C. Cheng for her excellent secretarial assistance.

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  1. Department of Oncology, National Taiwan University Hospital, and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan

    Hung-Yang Kuo

  2. Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada

    Kabir A. Khan & Robert S. Kerbel

  3. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Kabir A. Khan & Robert S. Kerbel

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R.S.K. has received research funding from Genentech and Novelty Nobility, and is a consultant for Novelty Nobility, OncoHost and PharmAbcine. H.-Y.K. and K.A.K. declare no competing interests.

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Kuo, HY., Khan, K.A. & Kerbel, R.S. Antiangiogenic–immune-checkpoint inhibitor combinations: lessons from phase III clinical trials. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00886-y

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