Overcoming resistance in HER2-positive gastric cancer: a case report on the synergistic effect of pembrolizumab and trastuzumab.

Introduction: The first-line standard therapy for advanced HER2-positive gastric cancer is chemotherapy combined with trastuzumab and pembrolizumab, while pembrolizumab alone does not benefit as a monotherapy in patients with mismatch repair proficiency (pMMR). This case explores the therapeutic potential of adding pembrolizumab to patients who were resistant to trastuzumab, focusing on the synergistic effect of an immune checkmate inhibitor, combined with HER2 antibody. Case Presentation: An 87-year-old metastatic gastric cancer patient, whose medical history was significant for intolerance to chemotherapy and had a poor status of performance. Immunohistochemical staining was presented as HER2 (3+), pMMR, and PD-L1 was 4. Initially treated with trastuzumab monotherapy, the patient showed no response and experienced progressive disease. Subsequently, a combined regimen of trastuzumab and a half-dose of pembrolizumab was administered every 3 weeks. Remarkably, it led to a significant reduction in tumor size, achieving partial remission (PR) after two cycles. This response was sustained over 21 months, as evidenced by the latest CT scans. Clinical Discussion: The concurrent administration of trastuzumab and pembrolizumab has demonstrated synergistic antitumor activity, achieving clinical efficacy in cases where each agent alone proved ineffective. Preclinical studies illustrated that tumor regression induced by HER2 antibodies requires T cell involvement, and the combination of immune checkpoint inhibitors with trastuzumab augments HER2-specific T cell responses, promotes immune cell recruitment, and induces the expansion of peripheral memory T cells, which showed synergistic rationales for a combination of pembrolizumab and trastuzumab. Conclusion: The observed synergy between pembrolizumab and trastuzumab highlights a promising treatment avenue that warrants further investigation.