Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies

Antibody-drug conjugates (ADCs) are one of the fastest-growing oncology therapeutics, merging the cytotoxic effect of conjugated payload with the high specific ability and selectivity of monoclonal antibody targeted on a specific cancer cell membrane antigen. The main targets for ADC development are antigens commonly expressed by lung cancer cells, but not in normal tissues. They include human epidermal growth factor receptor 2, human epidermal growth factor receptor 3, trophoblast cell surface antigen 2, c-MET, carcinoembryonic antigen–related cell adhesion molecule 5, and B7-H3, each with one or more specific ADCs that showed encouraging results in the lung cancer field, more in non–small-cell lung cancer than in small-cell lung cancer histology. To date, multiple ADCs are under evaluation, alone or in combination with different molecules (eg, chemotherapy agents or immune checkpoint inhibitors), and the optimal strategy for selecting patients who may benefit from the treatment is evolving, including an improvement of biomarker understanding, involving markers of resistance or response to the payload, besides the antibody target. In this review, we discuss the available evidence and future perspectives on ADCs for lung cancer treatment, including a comprehensive discussion on structure-based drug design, mechanism of action, and resistance concepts. Data were summarized by specific target antigen, biology, efficacy, and safety, differing among ADCs according to the ADC payload and their pharmacokinetics and pharmacodynamics properties.