Advances in therapeutic approaches to gastric cancer

Abstract

Gastric cancer remains a leading cause of cancer-related mortality worldwide, with nearly 1 million new cases diagnosed annually. Despite innovations in diagnosis, most patients still present at advanced stages, contributing to a poor prognosis. For early gastric cancer, endoscopic resection or minimally invasive surgery has become standard, offering comparable oncologic outcomes with faster recovery compared with open surgery. In locally advanced disease, resection of the primary lesion and D2 lymphadenectomy, defined as dissection of lymph nodes along two levels of blood vessels supplying the stomach, remains the cornerstone of curative surgery, whereas perioperative chemotherapy, particularly oxaliplatin-based regimens, has demonstrated improved survival benefits compared with surgery alone. The integration of immunotherapy into perioperative therapy for locally advanced disease and first-line palliative therapy for metastatic disease represents a paradigm shift, with programmed death 1/programmed death-ligand 1 inhibitors combined with chemotherapy significantly improving pathologic complete response rates and overall survival, especially in programmed death ligand 1–positive and microsatellite instability-high tumors. Targeted agents include claudin 18.2 antibody, with zolbetuximab establishing a new first-line standard for claudin 18.2–positive disease, and antibody–drug conjugates, such as trastuzumab deruxtecan for human epidermal growth factor receptor 2–positive disease, both of which have revolutionized treatment paradigms. Emerging strategies include dual immune checkpoint inhibition, bispecific antibodies, chimeric antigen receptor T-cell therapy, and fibroblast growth factor receptor 2b–targeting agents. Ultimately, the field is moving toward personalized, biomarker-driven approaches within multidisciplinary frameworks, although overcoming acquired resistance and addressing global disparities in therapeutic access remain important challenges.