Mapping the antibody-drug-conjugates landscape in non-small cell lung cancer: Where are we and where are we going?

Abstract

Antibody-drug conjugates (ADCs) represent a rapidly advancing therapeutic class in the treatment of non-small cell lung cancer (NSCLC), offering targeted delivery of cytotoxic agents to tumor cells while minimizing off-target toxicity. In recent years, several ADCs have emerged in both early (phase 1-2) and late (phase 3) clinical development, reflecting a growing recognition of their potential to improve outcomes in defined subsets of patients with advanced NSCLC. Late-phase ADCs include trastuzumab deruxtecan (targeting HER2 [human epidermal growth factor receptor 2]), datopotamab deruxtecan and sacituzumab govitecan (targeting TROP2 [trophoblast cell-surface antigen 2]), patritumab deruxtecan (targeting HER3), telisotuzumab vedotin (targeting c-MET [cellular-mesenchymal epithelial transition factor]), and sigvotatug vedotin (targeting IB6 [integrin beta-6]). Research efforts are ongoing to explore novel payloads, linker technologies, and targets to expand the applicability of ADCs across broader NSCLC populations, including those with limited treatment options (e.g., EGFR-mutant disease in the context of treatment resistance). Despite their promise, challenges remain in optimizing patient selection, overcoming resistance mechanisms, and managing unique toxicity profiles. Ongoing, biomarker-driven trials and combination strategies with immunotherapy or tyrosine kinase inhibitors hold the potential to further enhance the efficacy of ADCs. In this review, the authors highlight the current landscape and future directions of ADCs in NSCLC, emphasizing available results for compounds in late-stage clinical development and different disease settings.