Interstitial lung disease in patients treated with antibody-drug conjugates: a review

Antibody-drug conjugates (ADCs) are increasingly used across solid tumors, including lung cancer, but drug-related interstitial lung disease (ILD)/pneumonitis has emerged as a clinically relevant and potentially fatal toxicity.

This narrative review summarizes evidence from clinical trials, pooled analyses, pharmacovigilance studies, mechanistic investigations, and consensus recommendations on the epidemiology, pathophysiology, diagnosis, risk factors, and management of ADC-related ILD.

ILD has been most extensively characterized with trastuzumab deruxtecan (T-DXd), for which pooled analyses report an incidence of approximately 10-15%, a median onset of 5-6  months, and a fatal-event rate of about 2.2%. However, pulmonary toxicity is not restricted to HER2-directed ADCs and has also been reported with deruxtecan-based agents targeting TROP2 and HER3, as well as with non-deruxtecan ADCs. Pharmacovigilance data from 1,277 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. Risk is influenced by ADC type, payload, dose, age, pre-existing lung disease, and concomitant pulmonary-toxic therapies.

ADC-related ILD is a class-relevant toxicity requiring baseline risk assessment, serial high-resolution chest computed tomography, prompt treatment interruption, grade-based corticosteroid therapy, and multidisciplinary management. Structured surveillance and early intervention may substantially reduce severe and fatal outcomes.