QT Prolongation Risk of Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) have emerged as an important therapeutic class in oncology, offering targeted delivery of potent cytotoxic agents to cancer cells, thereby reducing systemic toxicity. However, the potential for cardiac toxicity, particularly QT interval prolongation, remains a critical safety concern during ADC development and clinical use. We review the mechanisms underlying ADC-induced QT prolongation, including payload-related direct ion channel interactions and indirect effects mediated by systemic exposure. By systematically examining clinical and preclinical data across ADC classes, including auristatins, maytansinoids, topoisomerase inhibitors, and DNA alkylators, we highlight the risk evaluation of 14 US Food and Drug Administration-approved ADCs, along with their regulatory review outcomes and labeling recommendations. Most approved ADCs appear to have a low corrected QT prolongation risk at therapeutic doses; clear signals are largely confined to inotuzumab and gemtuzumab ozogamicin, whereas auristatin-, maytansinoid-, and topoisomerase-1-based ADCs have shown minimal or no corrected QT changes. Regulatory approaches to ADC QT assessment are flexible and largely driven by payload novelty: novel payloads generally require comprehensive non-clinical testing and early dedicated QT studies, whereas established payloads can often rely on prior safety data, permitting extrapolation without new QT studies and use of pooled clinical data plus concentration-QT analyses when exposure and the linker-payload structure align with historical experience. Finally, we outline a practical framework for integrating translational and regulatory considerations for evaluating QT interval prolongation risk into the development of ADCs for patients with cancer, aiming to enhance cardiac safety for patients and improve the design of preclinical and clinical studies.