Aoki Yu, Nakayama Izuma, Shitara Kohei
Department of Medical Oncology, Tokyo Saiseikai Central Hospital, Minato-Ku, Tokyo, Japan.
Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan.
Curr Oncol Rep. 2025 Jan;27(1):15-29. doi: 10.1007/s11912-024-01626-2. Epub 2025 Jan 3.
Human epidermal growth factor receptor 2 (HER2) is a critical target in advanced gastric cancer (AGC). This review highlights the current treatment landscape, lessons learned from past clinical trials, and prospects for future treatment strategies for HER2-positive AGC.
Trastuzumab had been the standard treatment for HER2-positive AGC for a decade, and subsequently, trastuzumab deruxtecan, an antibody-drug conjugate (ADC), emerged with an impressive response. Recently, the addition of pembrolizumab to first-line chemotherapy plus trastuzumab has become a novel standard treatment. Past clinical trials of HER2-targeted therapies, which succeeded in HER2-positive breast cancer but failed in AGC, have deepened our understanding of resistance mechanisms. Based on these results, several clinical trials of novel HER2-targeted therapies, including immunologic approaches such as CAR-T cells and vaccines, are currently ongoing. Circulating tumor DNA is also expected to be a tool for real-time biomarker analysis. Additionally, ADCs with a bystander effect have the potential to expand the scope of HER2-targeted therapies to HER2-expressing, including HER2-low AGC. Learning from past trials, further development of novel HER2-targeted therapies is underway, expanding their scope to HER2-expressing AGC. Meanwhile, selecting optimal treatment is a challenging issue in cases with HER2-low AGC overlapping with other biomarkers like CLDN18.2.
人表皮生长因子受体2（HER2）是晚期胃癌（AGC）的关键靶点。本综述重点介绍了HER2阳性AGC的当前治疗格局、从过去临床试验中吸取的经验教训以及未来治疗策略的前景。
曲妥珠单抗十年来一直是HER2阳性AGC的标准治疗药物，随后，抗体药物偶联物（ADC）曲妥珠单抗德鲁替康出现，疗效显著。最近，在一线化疗加曲妥珠单抗基础上加用帕博利珠单抗已成为一种新的标准治疗方法。过去针对HER2的靶向治疗临床试验在HER2阳性乳腺癌中取得成功，但在AGC中失败，这加深了我们对耐药机制的理解。基于这些结果，目前正在进行多项新型HER2靶向治疗的临床试验，包括CAR-T细胞和疫苗等免疫疗法。循环肿瘤DNA也有望成为实时生物标志物分析的工具。此外，具有旁观者效应的ADC有可能将HER2靶向治疗的范围扩大到HER2表达的AGC，包括HER2低表达的AGC。从过去的试验中吸取经验，新型HER2靶向治疗的进一步开发正在进行中，将其范围扩大到HER2表达的AGC。与此同时，在HER2低表达AGC与CLDN18.2等其他生物标志物重叠的情况下，选择最佳治疗方案是一个具有挑战性的问题。
