Second-line treatment of HER2-positive advanced gastroesophageal adenocarcinoma

There is an unmet need for the treatment of patients with HER2-positive gastroesophageal tumors whose disease progressed on a first-line trastuzumab-based regimen. Several prospective trials took a targeted approach and evaluated various HER2-targeted agents as second-line therapy. However, these trials failed to demonstrate a survival benefit and were negative in primary endpoints. Recently, the antibody–drug conjugate trastuzumab deruxtecan has shown promise as a second-line treatment in patients with HER2-positive metastatic gastroesophageal tumors, with a remarkable overall response rate and a relevant prolongation of prognostic outcome. Several clinical trials will introduce more targeted therapy approaches with novel structures, which will hopefully further extend patients’ survival. This mini-review briefly summarizes the past practice of second-line treatment of HER2-positive gastroesophageal tumor patients, describes current knowledge based on recently published studies, and provides a short overview on the novel anti-HER2 compounds that are currently being clinically investigated and could yield positive results in the near future.