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

• Published in: Nature reviews. Clinical oncology Vol. 20; no. 8; pp. 558 - 576
• Main Authors: Tarantino, Paolo, Ricciuti, Biagio, Pradhan, Shan M., Tolaney, Sara M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2023; Nature Publishing Group
• Subjects: 692/308/153; 692/699/67/1059/2325; 692/699/67/1059/2326; 692/699/67/1059/602; Antibodies; Antigen (tumor-associated); Antineoplastic Agents - adverse effects; Chemotherapy; Clinical trials; Cytotoxicity; Drug development; Humans; Immunoconjugates - adverse effects; Medicine; Medicine & Public Health; Neoplasms; Oncology; Patients; Review Article; Solid tumors; Tumors
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-023-00783-w

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.
Advances in technology have enabled the development of several novel antibody–drug conjugates (ADCs) with encouraging clinical activity in patients with advanced-stage solid tumours. Indications for these therapies are expanding rapidly to earlier lines of therapy. Nonetheless, the toxicities of these various agents are not trivial and can be fatal, even in patients with early stage disease. In this Review, the authors summarize the toxicities of ADCs in patients with solid tumours both as monotherapies and in combination with other agents and discuss various ongoing research efforts attempting to optimize the therapeutic index of these agents.
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.