An evaluation of pembrolizumab with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for HER2 positive gastric or gastroesophageal junction adenocarcinoma expressing PD-L1 (CPS ≥1)

INTRODUCTION: Despite the introduction of several novel agents, survival for patients with metastatic gastric or gastroesophageal junction adenocarcinoma remains limited. In human epidermal growth factor receptor 2 (HER-2) positive disease, pembrolizumab plus trastuzumab and fluoropyrimidine- and platinum-based chemotherapy has recently demonstrated a survival benefit, particularly in tumors expressing programmed death-ligand 1 (PD-L1) with a combined positive score (CPS) ≥1 in the phase III KEYNOTE-811 trial. AREAS COVERED: This review summarizes the evolution of HER2-directed therapies in gastric cancer and focuses on the efficacy and safety of pembrolizumab in combination with trastuzumab and chemotherapy. We highlight the mechanistic rationale for dual HER2 and PD-1 blockade, pivotal trial evidence, and other novel HER2-directed therapies currently under active clinical evaluation in the first-line setting. A literature search was conducted using PubMed and ClinicalTrials.gov. EXPERT OPINION: Pembrolizumab plus trastuzumab and chemotherapy has established a new first-line standard of care for patients with HER2-positive, PD-L1 CPS ≥1 metastatic gastric or gastroesophageal junction adenocarcinoma. Nonetheless, primary and acquired resistance driven by HER2 heterogeneity, immune evasion, and dynamic molecular evolution remain major challenges. Next-generation HER2-targeted therapies, including bispecific antibodies, novel antibody - drug conjugates, and dual HER2 antibodies will be crucial to further improve outcomes in this population.