Targeting Esophageal Cancer: Promising Drugs for the Clinical Landscape and Key Knowledge Gaps

Esophageal cancer remains a major global health burden, ranking seventh in cancer-related mortality. The prognosis is poor with five-year survival rates below 5% for metastatic disease. Tumor heterogeneity and the development of treatment resistance have limited durable responses to conventional chemotherapy. The emergence of biomarker-driven therapies has begun to transform management and enable more personalized treatment approaches. This narrative review summarizes current clinical strategies for esophageal cancer, emphasizing clinically validated biomarkers -HER2, PD-L1, CLDN18.2, and MMR/MSI status-that inform therapeutic selection for advanced metastatic disease. Both esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) are addressed; however, this review centers on biomarker-directed therapies for EAC, reflecting its predominance in Western populations and recent therapeutic progress. We highlight pivotal phase II and III clinical trials that have established the current landscape of esophageal cancer treatment. In addition, we review key early phase clinical data for promising new modalities such as antibody-drug conjugates, novel monoclonal antibodies, and cellular therapies-highlighting their biomarker associations and mechanisms of action. Finally, we discuss the ongoing challenges-including elucidating tumor heterogeneity, improving biomarkers, targeting novel tumor intrinsic vulnerabilities, overcoming treatment resistance, and preventing esophageal cancer development-and identify key research directions that present unique opportunities for the development of new biomarker-driven treatments for esophageal cancer.