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

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.