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Antibody-drug conjugates (ADCs) are reshaping the therapeutic approach to advanced gastrointestinal cancers by integrating tumor-specific monoclonal antibodies with potent cytotoxic payloads to improve targeted tumor cell destruction while minimizing systemic exposure. Compared to traditional chemotherapy, trastuzumab deruxtecan has significantly improved objective response rates and overall survival in HER2-positive gastric and gastroesophageal junction tumors after trastuzumab-based therapy. This supports its role as an important second-line or later treatment option. The ongoing advancement of ADCs targeting CLDN18.2, TROP2, and CEACAM5 indicates that this therapeutic category will continue to expand across gastrointestinal neoplasms. Nonetheless, these advancements are accompanied by a specific and clinically significant toxicity profile. Hematologic suppression, gastrointestinal side effects, hepatotoxicity, and notably interstitial lung disease (ILD) are essential consequences that may need inpatient assessment and care. Interstitial lung disease (ILD), although uncommon, may be severe or lethal if not identified immediately and treated swiftly with medication cessation and corticosteroids. In hospitalized patients, distinguishing ADC-related toxicity from infection or disease progression is often difficult owing to overlapping clinical manifestations, requiring meticulous evaluation and interdisciplinary cooperation. As ADCs are integrated into earlier treatment lines and across a broader patient population, hospital systems must evolve to ensure prompt identification, consistent management protocols, and efficient collaboration between oncology and inpatient teams. This study analyzes the mechanisms, clinical effectiveness, and safety profile of ADCs in gastrointestinal oncology, pointing out the importance of institutional preparedness to safely incorporate these medicines into standard clinical practice. These features also align ADC therapy with personalized medicine by emphasizing biomarker-guided patient selection and individualized toxicity monitoring.