Antibody-drug conjugate components in association with the incidence of ADC-related interstitial lung disease: A systematic review and meta‐analysis

Abstract

Background

Antibody-drug conjugates (ADCs) have emerged as an innovative approach in cancer therapy. Although the incidence of ADC-related interstitial lung disease (ILD) is low, it remains a clinically significant and potentially fatal adverse event. This study focuses on evaluating the incidence of ADC-related ILD and examining how specific ADC components contribute to the risk of ILD.

Methods

Five databases were conducted to identify clinical studies on ADC-related ILD published up to September 2024. The incidence of treatment-related adverse events was calculated by a random effects (RE) model.

Results

A total of 120 clinical studies involving 20,119 patients were included. The overall incidence of ADC-related ILD was 4.40 % (1215/20119) for all-grade and 2.35 % (603/20119) for grade ≥ 3 ILD. Among these, 2287 patients had hematologic tumors and 17,832 patients had solid tumors. Particularly, gastrointestinal cancers (12.81 %, 107/835), followed by lung cancer (9.70 %, 290/2991) were observed with a high incidence of ILD. A detailed subgroup analysis was performed, stratified by payload, drug-to-antibody ratio (DAR) value, linker type, and target. ADCs with cleavable linkers exhibited a higher incidence, notably, ADCs with glutathione (GSH) linkers were the highest. Furthermore, ADCs with high DAR had a higher incidence of ILD. Interestingly, payload type alone did not significantly affect the incidence, while a marked increase in ILD risk was observed when specific payloads (such as topoisomerase I inhibitors) were combined with high DAR values or cleavable linkers.

Conclusion

This study reveals variability of ADC-related ILD incidence, largely driven by the specific components of the ADCs, offer valuable insights into potential ILD occurrence patterns and guide for optimizing ADC design.