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  • Review Article
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Optimizing the safety of antibody–drug conjugates for patients with solid tumours

Nature Reviews Clinical Oncology volume 20, pages 558–576 (2023)Cite this article

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Abstract

Over the past 5 years, improvements in the design of antibody–drug conjugates (ADCs) have enabled major advances that have reshaped the treatment of several advanced-stage solid tumours. Considering the intended rationale behind the design of ADCs, which is to achieve targeted delivery of cytotoxic molecules by linking them to antibodies targeting tumour-specific antigens, ADCs would be expected to be less toxic than conventional chemotherapy. However, most ADCs are still burdened by off-target toxicities that resemble those of the cytotoxic payload as well as on-target toxicities and other poorly understood and potentially life-threatening adverse effects. Given the rapid expansion in the clinical indications of ADCs, including use in curative settings and various combinations, extensive efforts are ongoing to improve their safety. Approaches currently being pursued include clinical trials optimizing the dose and treatment schedule, modifications of each ADC component, identification of predictive biomarkers for toxicities, and the development of innovative diagnostic tools. In this Review, we describe the determinants of the toxicities of ADCs in patients with solid tumours, highlighting key strategies that are expected to improve tolerability and enable improvements in the treatment outcomes of patients with advanced-stage and those with early stage cancers in the years to come.

Key points

  • Indications for the use of antibody–drug conjugates (ADCs) are rapidly expanding, with development progressively moving from the advanced-stage to the early stage setting, and from monotherapy to combination strategies.

  • Despite being designed with the rationale of expanding the therapeutic indices of conventional chemotherapies, most ADCs have a toxicity profile similar to that of their cytotoxic payload.

  • Unconventional and potentially life-threatening toxicities can also be observed with certain ADCs, requiring an increased understanding of these events and the optimization of diagnostic and management practices.

  • Multiple pharmacological modification strategies are being pursued in an attempt to improve the tolerability of ADCs, including molecular alterations of the antibody moiety, linker and/or cytotoxic payload.

  • Exploration of different doses within randomized trials and investigation of response-adapted dosing strategies could enable optimized use of ADCs, which could maximize their therapeutic value for each indication.

  • Extensive efforts to identify biomarkers of toxicities in patients receiving ADCs and to develop diagnostic tools enabling the anticipation and/or early detection of toxicities are currently ongoing.

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Fig. 1: Structure and main toxicities of ADCs currently approved for patients with solid tumours.
Fig. 2: Determinants of the toxicities of ADCs.
Fig. 3: Strategies being tested to potentially optimize the safety of ADCs.

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Acknowledgements

No funding was provided for this work. We thank V. H. Goldstein of Dana-Farber Cancer Institute for submission assistance. The authors would also like to thank R. Colombo of Zymeworks (Vancouver, Canada) for providing precious insights during the writing of this paper. This article reflects the views of the authors and should not be construed to represent FDA views or policies.

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Authors and Affiliations

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

    Paolo Tarantino & Sara M. Tolaney

  2. Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA

    Paolo Tarantino & Sara M. Tolaney

  3. Harvard Medical School, Boston, MA, USA

    Paolo Tarantino, Biagio Ricciuti & Sara M. Tolaney

  4. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Paolo Tarantino

  5. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Biagio Ricciuti

  6. Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Shan M. Pradhan

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P.T. and B.R. researched data and wrote this manuscript. All authors made substantial contributions to discussions of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Sara M. Tolaney.

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P.T. has acted as an adviser and/or consultant of AstraZeneca, Daiichi Sankyo, Gilead and Lilly. B.R. reports fees from Regeneron not related to the present article. S.M.T. has acted as a consultant and/or adviser of 4D Pharma, Aadi Bio, ARC Therapeutics, AstraZeneca, Bayer, BeyondSpring Pharmaceuticals, Blueprint Medicines, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Eli Lilly, Ellipses Pharma, Genentech/Roche, Gilead, Incyte Corporation, Infinity Therapeutics, Menarini/Stemline, Merck, Myovant, Novartis, Odonate Therapeutics, OncoSec Medical Inc., OncXerna, Pfizer, Reveal Genomics, Sanofi, Seattle Genetics, Umoja Biopharma, Zentalis, Zetagen, and Zymeworks and received research funding from AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Gilead, Genentech/Roche, Lilly, Merck, NanoString Technologies, Novartis, OncoPep, Pfizer, Sanofi, and Seattle Genetics. S.M.P. declares no competing interests.

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Tarantino, P., Ricciuti, B., Pradhan, S.M. et al. Optimizing the safety of antibody–drug conjugates for patients with solid tumours. Nat Rev Clin Oncol 20, 558–576 (2023). https://doi.org/10.1038/s41571-023-00783-w

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