Current and Emerging Targeted Therapy in Advanced Gastroesophageal Adenocarcinoma

Background/Objectives: Advanced gastroesophageal adenocarcinoma (GEA) carries a poor prognosis, with median overall survival of 13–20 months despite standard chemotherapy. Since trastuzumab’s approval, biomarker-driven precision therapies have expanded rapidly. This review comprehensively summarises current and emerging targeted agents across the key molecular targets driving advanced GEA. Methods: A comprehensive literature review was conducted using PubMed, Google Scholar and Cochrane Library in accordance with PRISMA guidelines, searching English-language human studies published between February and July 2026, supplemented by updates during editing to reflect current standards. Results: HER2-directed therapy has progressed from trastuzumab through dual blockade, immunotherapy combinations, next-generation ADCs (notably trastuzumab deruxtecan) and bispecific antibodies such as zanidatamab, which has now overtaken trastuzumab in the first-line setting. CLDN18.2-targeted zolbetuximab has demonstrated survival benefit in biomarker-selected patients, with newer ADCs, BiTEs and the first approved solid-tumour CAR-T therapy (satricabtagene autoleucel) extending this target further. VEGFR2 inhibition with ramucirumab remains a cornerstone in later lines, while novel VEGF/PD-1(L1) bispecifics are under investigation. FGFR2b-targeted bemarituzumab showed early promise that weakened on phase 3 confirmation, and MET/EGFR-directed agents, including savolitinib and amivantamab, require stringent biomarker selection to demonstrate benefit amid tumour heterogeneity. Conclusions: Novel targeted agents, particularly to HER2 and CLDN18.2, have demonstrated survival benefit despite ongoing challenges. Other lines are more investigational.