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. 2025 Jul 3;18(1):71.
doi: 10.1186/s13045-025-01720-3.

Treatment-related adverse events of antibody drug-conjugates in clinical trials

Harold Nathan Tan  1   2   3 , Marta Ascanio Morcillo  4 , Juanita Lopez  4   5 , Anna Minchom  4   5 , Adam Sharp  4   5 , Alec Paschalis  4   5 , Georgina Silva-Fortes  4 , Bindu Raobaikady  4   5 , Udai Banerji  6   7
Affiliations

Treatment-related adverse events of antibody drug-conjugates in clinical trials

Harold Nathan Tan et al. J Hematol Oncol. .

Abstract

Background: Antibody-drug conjugates (ADCs) aim to enhance the therapeutic index of cytotoxic agents but can cause unexpected toxicities. This study evaluated adverse events (AEs) from phase 1 trials at The Royal Marsden Drug Development Unit (DDU) over a decade and pivotal phase 2 and 3 trials leading to FDA registration, correlating AEs with ADC components such as target, antibody, linker, payload, and Drug-to-Antibody Ratio (DAR).

Methods: We performed a retrospective cohort analysis of patients treated with ADCs in phase 1 trials (January 2014 to January 2024) compared to published phase 2-3 trials of FDA-approved ADCs. Univariate and multivariate logistic regression analyzed ADC components and treatment toxicities.

Results: One hundred thirty one phase 1 trial patients and 2666 phase 2-3 trial participants were included. High incidences of any-grade treatment-related AEs were observed (89% in phase 1, 93% in phase 2-3), with 58% experiencing grade 3 or higher toxicities in phase 1 and 46% in later phases. Major AEs included fatigue, hematologic toxicities, nausea/vomiting, ocular toxicities, and peripheral neuropathy. Antibody targets were linked to neuropathy, non-cleavable linkers to ocular, pulmonary, and hematologic toxicities, and tubulin-binding payloads to peripheral neuropathy. ADCs with DAR > 4 were associated with higher pulmonary and hematologic AEs.

Conclusion: Despite their design to minimize toxicity, ADCs were linked to significant AEs. Specific ADC components may contribute to distinct toxicities, necessitating more robust trial data to inform future ADC design.

Keywords: ADCs; AEs; Clinical trials.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Ethical approval to collect, anonymize, and tabulate toxicities caused by ADCs on phase I trials was approved by the Committee for Clinical Research of The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation trust; SE1324. The study was performed in accordance with the Declaration of Helsinki. Competing interests: HNT, MAM, GSF, BR have no conflicts of interest to declare. UB has attended advisory boards and been compensated by Ellipsis Pharma, PharmEnable, and Carrick Therapeutics. He has received preclinical research funding from Verastem and Avacta and research funding to run academic trials from Verastem, Chugai, BTG phamaceuticals and Carrick Therapeutics. JL has served as consultant or an advisory role for Genmab, Novartis, Basilea, Roche-Genentech, CureTeq, Ellipses Pharma, Pierre Fabre and GSK. She has received grant/research funding from Astex Pharmaceuticals, Basilea, and Roche-Genentech. She has received travel support from Basilea and Roche-Genentech. A.M. has served on advisory boards for Janssen, Merck, Takeda, MSD, Genmab, Merck, Pfizer, Astrazaneca and Immutep. She has received honoraria from Chugai, Faron, Merck, GSK, Seagen, Takeda and Janssen. A.M has received travel support from Amgen and Janssen. She has received research funding from Astex, Merck and MSD. A. S. is an employee of the ICR, which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K/AKT pathway inhibitors (no personal income). A.S. has received travel support from Sanofi, Roche-Genentech and Nurix, and speaker honoraria from Astellas Pharma and Merck Sharp & Dohme. He has served as an advisor to DE Shaw Research, CHARM Therapeutics, Ellipses Pharma and Droia Ventures. A. S. has been the CI/PI of industry-sponsored clinical trials. A.P. is named on a patent held by the Institute of Cancer Research (ICR) together with Cancer Research UK identifying JMJD6 as a therapeutic target in advanced prostate cancer.

References

    1. Ruan DY, Wu HX, Meng Q, Xu RH. Development of antibody-drug conjugates in cancer: Overview and prospects. Cancer Commun. 2024;44(1):3–22. - PMC - PubMed
    1. Bardia A, Hu X, Dent R, Yonemori K, Barrios CH, O'Shaughnessy JA, Wildiers H, Pierga JY, Zhang Q, Saura C, Biganzoli L, Sohn J, Im SA, Lévy C, Jacot W, Begbie N, Ke J, Patel G, Curigliano G, DESTINY-Breast06 Trial Investigators. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024;391(22):2110–2122. - PubMed
    1. Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423–33. - PubMed
    1. Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS, ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021;384(16):1529–1541.
    1. Zhu Y, Liu K, Wang K, Zhu H. Treatment-related adverse events of antibody–drug conjugates in clinical trials: A systematic review and meta-analysis. Cancer. 2023;129(2):283–95. - PMC - PubMed

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