Emerging biological drugs for the treatment of patients with metastatic HER2+ gastroesophageal adenocarcinomas.

INTRODUCTION: Advanced gastroesophageal adenocarcinomas (GEAs) continue to represent an area in need of new drug development. Targeting human epidermal growth factor receptor-2 (HER2) in GEAs has been standard since 2010 and continues to be an area of further development.

AREAS COVERED: Trastuzumab became the first targeted agent approved for GEA. Added to front-line fluoropyrimidine plus platinum chemotherapy in HER2+ metastatic disease, trastuzumab improved survival. Pembrolizumab was approved in HER2 positive GEA for those PD-L1 positive with modest benefit. Since trastuzumab's approval, other anti-HER2 agents had limited impact until 2021 with the FDA approval of trastuzumab deruxtecan. Trastuzumab deruxtecan represents an option after trastuzumab-based therapy fails. Other agents are currently being investigated.

EXPERT OPINION: With the abundance of anti-HER2 therapies in the investigative pipeline, understanding key resistance mechanisms seen in HER2+ GEA will be the path to success. Technology advancements to provide real‑time precision medicine are likely in the coming years. We hope these advancements can help combat and/or understand some of the intratumoral heterogeneity, HER2 expression changes, and tumor microenvironment resistance pathways seen in HER2+ GEA.