Advances in the management of metastatic gastric cancer: current strategies and emerging therapeutics

Abstract

Metastatic gastric cancer remains a major global health challenge with poor long-term outcomes. Over the past 5 years, the treatment landscape has rapidly evolved with the integration of biomarker-informed strategies that guide the use of immune checkpoint inhibitors and targeted therapies in molecularly defined subgroups, including microsatellite unstable, PD-L1-expressing, HER2-positive and claudin 18.2-positive disease. Standard first-line treatment continues to rely on fluoropyrimidine–platinum chemotherapy backbones, with biomarker-driven agents selectively layered on for improved efficacy. Despite these advances, most patients continue to have disease progression, and durable responses are uncommon. In addition to identifying and validating new targets such as FGFR2b, ongoing efforts are focusing on novel strategies involving established targets, including HER2 and claudin 18.2, using next-generation treatment modalities such as antibody–drug conjugates, bispecific antibodies and cellular therapies. Complementary platforms including circulating tumour DNA and theranostic agents are also being explored to better guide treatment selection, facilitate non-invasive monitoring and enable early response assessments. In this Review, we summarize the current standard of care for patients with metastatic gastric cancer and also highlight emerging approaches aimed at improving the outcomes in these patients. The development of immune checkpoint inhibitors and novel targeted therapies and the incorporation of these agents into first-line therapy for biomarker-selected patients with metastatic gastric cancer has improved outcomes. Nonetheless, many challenges remain, including both primary and acquired resistance as well as a lack of relevant biomarkers in certain subgroups. In this Review, the authors describe the current approach to first-line therapy for patients with metastatic gastric cancer as well as emerging approaches that might improve the standard of care in the coming years.