Antibody–drug conjugates in lung cancer: clinical development, therapeutic advances, and emerging challenges

Abstract

Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic agents directly to tumor cells by conjugating an antigen-specific monoclonal antibody with a potent payload. By recognizing tumor-associated antigens and undergoing intracellular processing, ADCs enhance antitumor activity while minimizing damage to normal tissues. This review focuses on the research progress of ADCs targeting non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), providing an in-depth analysis of their mechanisms of action, molecular design, and clinical efficacy, with particular emphasis on novel ADCs targeting HER2, TROP2, and DLL3. Despite challenges such as target specificity and drug resistance, clinical trial data demonstrate that ADCs exhibit significant therapeutic efficacy in the treatment of both NSCLC and SCLC. The article also discusses emerging strategies to overcome current limitations, including innovative linker technologies, development of bispecific ADCs, and exploration of combination treatment plans. Given that lung cancer is the leading cause of cancer-related mortality worldwide, ADCs technology holds promise for delivering breakthrough advances in improving therapeutic outcomes and alleviating the societal burden of the disease. With ongoing research into ADCs, future clinical applications may provide more precise and effective treatment options for patients with lung cancer. Landscape of antibody-drug conjugate (ADC) targets, payload classes, and clinical-development maturity in lung cancer. ADC targets in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are categorized according to representative cytotoxic payload classes and overall clinical development maturity. In NSCLC, HER2 and TROP2 represent the most clinically advanced ADC targets, while HER3, c-MET, and CEACAM5 remain under active clinical investigation. In SCLC, DLL3, SEZ6, and B7-H3 have emerged as promising therapeutic targets with distinct developmental trajectories. Payload classes are grouped according to mechanism of action, including topoisomerase I inhibitors, DNA alkylators, and microtubule inhibitors. Development maturity is indicated by a four-dot scale representing approved/established, late-stage clinical, early-to-mid clinical, and exploratory/emerging stages. Landscape of antibody-drug conjugate (ADC) targets, payload classes, and clinical-development maturity in lung cancer. ADC targets in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are categorized according to representative cytotoxic payload classes and overall clinical development maturity. In NSCLC, HER2 and TROP2 represent the most clinically advanced ADC targets, while HER3, c-MET, and CEACAM5 remain under active clinical investigation. In SCLC, DLL3, SEZ6, and B7-H3 have emerged as promising therapeutic targets with distinct developmental trajectories. Payload classes are grouped according to mechanism of action, including topoisomerase I inhibitors, DNA alkylators, and microtubule inhibitors. Development maturity is indicated by a four-dot scale representing approved/established, late-stage clinical, early-to-mid clinical, and exploratory/emerging stages.