Antibody-Mediated Therapy in Gastric Cancer: Past, Present, and Future

The limited efficacy of cytotoxic chemotherapy in the context of gastric cancer treatment is largely driven by profound molecular and biological heterogeneity. In contrast, the development of antibody-mediated therapies has ushered in a new era of precision oncology by enabling selective molecular targeting and immune modulation. This review includes a comprehensive overview of the evolution of antibody-based therapeutics in gastric cancer, highlighting early breakthroughs, subsequent setbacks, and recent advances that have reshaped the treatment landscape. We summarize the current standard regimens targeting HER2, VEGFR2, PD-1/PD-L1, and CLDN18.2 and examine pivotal clinical trials evaluating monoclonal antibodies directed against these pathways. We also discuss emerging therapeutic modalities, including next-generation antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies. Trastuzumab first established HER2-targeted therapy in gastric cancer, but the failure of trastuzumab emtansine (T-DM1) led to a decade-long stagnation until the advent of trastuzumab deruxtecan (T-DXd), which demonstrated robust clinical activity and defined a new standard of care. While bevacizumab failed to improve survival, the anti-VEGFR2 antibody ramucirumab emerged as an effective second-line therapy. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, have been incorporated into first-line treatment for PD-L1-positive disease based on landmark trials such as CheckMate 649 and KEYNOTE-811. More recently, the CLDN18.2-targeted antibody zolbetuximab has expanded therapeutic options for biomarker-selected patients. Concurrently, a diverse pipeline of immune-based strategies-such as TROP2-directed ADCs, bispecific antibodies, and CAR-T cell therapies-is undergoing active clinical development. Together, advances in biomarker-driven antibody therapeutics are accelerating personalized cancer care and improving clinical outcomes in patients with gastric cancer.