Trastuzumab deruxtecan in the treatment of HER2-positive gastric cancer: a comprehensive review

Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-targeted antibody - drug conjugate with a potent topoisomerase I inhibitor payload, has addressed considerable unmet needs in advanced HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC), particularly among patients showing disease progression following trastuzumab-based therapy. The present review summarizes the clinical development, real-world management, and future directions of T-DXd. The superiority of T-DXd was first demonstrated in the DESTINY-Gastric01 trial and subsequently confirmed in the recent global phase III DESTINY-Gastric04 trial, where it showed remarkable efficacy over chemotherapy, establishing it as the second-line standard of care. However, this efficacy must be balanced against its distinct safety profile, with interstitial lung disease representing most critical adverse event requiring vigilant monitoring and proactive management. Resistance mechanisms, including decreased HER2 expression and impaired internalization, remained the important challenges to overcome. Ongoing studies are exploring the role of T-DXd in first-line treatments, HER2-low tumors, and perioperative settings, with the aim of further expanding its therapeutic applications. These efforts hold promise for broadening the clinical utility of T-DXd and redefining the treatment algorithms for a wider population of GC/GEJC patients.