Efficacy and safety of antibody-drug conjugates in HER2-positive and HER2-low advanced gastric cancer: a systematic review and update

PURPOSE: Gastric cancer is a highly prevalent malignancy of the digestive tract in China. Conventional chemotherapeutic drugs and human epidermal growth factor receptor 2 (HER2)‑targeted agents such as trastuzumab remain limited by significant challenges in the treatment of GC, including high rates of drug resistance, significant toxicity and adverse effects, and suboptimal tolerability. The advent of antibody-drug conjugates (ADCs) has marked a paradigm shift in the therapeutic landscape. This review systematically summarises the structural design, mechanisms of action, and current clinical applications of ADCs in HER2-positive or HER2-low advanced gastric cancer. METHODS: The present review focuses on key clinical trial data for new-generation ADCs, specifically trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), drawing from the DESTINY-Gastric series and the RC48-C008 study. The review systematically synthesised data on efficacy, safety profiles, resistance mechanisms, and future therapeutic directions. RESULTS: New-generation ADCs have demonstrated significant improvements in objective response rates (ORR) and overall survival (OS) compared with traditional chemotherapy in later-line treatment settings. Emerging evidence also suggests the presence of activity in HER2-low-expressing populations. A systematic assessment of adverse drug reactions highlights both common events (e.g. gastrointestinal reactions, haematologic toxicity) and distinctive adverse events (e.g. interstitial lung disease), with corresponding management strategies. A comprehensive analysis of multiple resistance mechanisms, including HER2 heterogeneity, endocytic barriers, drug efflux, and target mutations, is conducted. CONCLUSION: The present study demonstrates that ADCs represent a transformative therapeutic modality for HER2-positive or HER2-low cases. Ongoing advancements in ADC structural optimisation, combination strategies with immune checkpoint inhibitors show great promise in terms of further improving clinical outcomes. The objective of this review is to furnish clinicians and researchers with a detailed reference for future clinical practice and investigation.