Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

中文翻译：

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HER2 阳性晚期/转移性胃癌系统治疗的突破：从单一化疗到三联疗法。

胃癌在形态学、生物学、基因组学和治疗反应方面具有异质性。人表皮生长因子受体 2 (HER2) 过表达、微卫星不稳定 (MSI) 状态、程序性死亡配体 1 (PD-L1) 水平和成纤维细胞生长因子受体 2 (FGFR2) 的变化可用作生物标志物。自 2010 年 ToGA 试验中研究的氟嘧啶/铂加曲妥珠单抗组合被批准作为 HER2 阳性患者的护理标准以来，没有其他药物在第一个试验（HELOISE、LOGiC、JACOB 试验）和第二个试验中显示出疗效。 -（TyTAN、GATSBY、T-ACT 试验）线治疗。尽管在治疗乳腺癌方面取得了成功，但各种抗 HER2 药物，包括单克隆抗体（帕妥珠单抗）、抗体药物偶联物（ADC；曲妥珠单抗 emtansine [T-DM1]）和小分子（拉帕替尼）未能转化为直到进行 KEYNOTE-811（一线）和 DESTINY-Gastri01（≥二线）试验之前，临床获益。将 HER2 导向治疗与单克隆抗体或 ADC 形式的免疫检查点抑制剂相结合现已被批准为标准治疗。尽管新药（工程单克隆抗体、双特异性抗体、融合蛋白和小分子）在开发的早期阶段取得了令人鼓舞的成果，但 HER2 阳性胃癌的治疗需要进一步优化，以实现以化疗为主的精准医疗。治疗抵抗是一个复杂的过程，可以通过联合化疗、靶向药物和免疫检查点抑制剂（包括新型药物）来克服。对于接受抗 HER2 治疗且一线治疗后疾病进展的患者，必须重新评估 HER2 状态。作为一般指南，需要全身治疗的患者应接受化疗加靶向药物、抗血管生成药物、免疫检查点抑制剂或其组合。