Antibody-drug conjugates in lung cancer: current landscape and future perspectives

Antibody-drug conjugates (ADCs) have emerged as a significant therapeutic class in lung cancer, integrating the target specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic agents. This review delineates ADC structure, mechanisms of action, and clinical advancements in nonsmall-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), with a focus on novel bispecific formats to address tumor heterogeneity and therapeutic approaches to overcome resistance mechanisms.

Multiple ADCs have demonstrated significant clinical activity in biomarker-defined patient subsets. The human epidermal growth factor receptor 2 (HER2)-targeted ADC trastuzumab deruxtecan has demonstrated unprecedented efficacy in HER2 -mutant NSCLC, resulting in global regulatory approvals. Novel ADC targets such as TROP2, HER3, MET, CEACAM5, integrin β6, DLL3, B7-H3, and SEZ6 are undergoing clinical evaluation. Advancements in payload design, linker stability, and conjugation methodologies have enhanced therapeutic indices. Concurrently, bispecific ADCs are emerging to address challenges posed by intratumoral heterogeneity and antigen-loss-mediated resistance mechanisms.

ADCs are transforming lung cancer therapy by delivering potent cytotoxics with manageable safety. Next-generation bispecific and biparatopic formats may broaden eligibility, improve tumor penetration, and delay resistance. Incorporating predictive biomarkers and real-time monitoring will be key to their use in earlier disease and to establishing ADCs as a cornerstone of precision oncology.