Review of interstitial lung disease in patients treated with antibody-drug conjugates for solid tumors

Antibody-drug conjugates (ADCs) are increasingly used for solid tumors, but drug-related interstitial lung disease (ILD)/pneumonitis has emerged as a clinically relevant and potentially fatal toxicity. A review of clinical trials, pooled analyses, pharmacovigilance studies, mechanistic investigations, and consensus recommendations summarized evidence of the epidemiology, diagnosis, risk factors, and management of ADC-related ILD. According to the review, ILD has been most extensively characterized with trastuzumab deruxtecan (T-DXd), for which pooled analyses report an incidence of 10-15%, a median onset of 5-6 months, and a fatal event rate of 2.2%. Pulmonary toxicity has also been reported with deruxtecan-based agents targeting TROP2 and HER3, as well as non-deruxtecan ADCs. Pharmacovigilance data from 1277 cases showed that ILD, pneumonitis, and acute respiratory distress syndrome accounted for 40.6%, 27.9%, and 7.6% of pulmonary events, respectively; acute respiratory distress syndrome had the earliest onset and highest case-fatality. Mechanistic data support antigen-independent, dose-dependent ADC uptake by alveolar macrophages through Fcγ receptors, followed by intracellular payload release and cytokine-mediated lung injury. The authors conclude that ADC-related ILD is a class-relevant toxicity requiring baseline risk assessment, serial surveillance and prompt treatment interruption.