扎尼达单抗（Zanidatamab）在食管胃腺癌治疗中的应用。
完整摘要 · 中文译文
食管胃癌（EGC）仍是全球癌症相关死亡的主要原因之一。约15-20%的晚期EGC过表达人表皮生长因子受体2（HER2）。自2010年以来，曲妥珠单抗联合铂类和氟嘧啶类化疗一直是HER2阳性晚期EGC一线治疗的基石，具有适度的总生存获益。在KEYNOTE-811试验中，在曲妥珠单抗和化疗基础上加用帕博利珠单抗改善了PD-L1阳性肿瘤的结局。尽管取得了这些进展，中位总生存期仍低于20个月。Zanidatamab是一种新型双表位HER2靶向抗体，设计用于结合HER2的两个不同胞外结构域，促进受体聚集、增强内化以及免疫介导的细胞毒性。本药物评价综述了zanidatamab在HER2阳性EGC中的药理学、药代动力学、临床开发、疗效、安全性和监管状态。III期HERIZON-GEA-01试验评估了zanidatamab（联合或不联合替雷利珠单抗）加化疗作为HER2阳性晚期EGC一线治疗。该试验显示，与基于曲妥珠单抗的治疗相比，无进展生存期和总生存期均取得具有临床意义的改善，促使FDA批准zanidatamab加化疗（联合或不联合替雷利珠单抗）作为HER2阳性不可切除局部晚期或转移性胃、胃食管结合部或食管腺癌的一线治疗。关于最佳患者选择、替雷利珠单抗的作用等关键问题仍然存在 跨PD-L1亚组、抗体偶联药物序贯治疗及长期安全性。 食管癌、胃癌及胃与食管连接处癌（统称食管胃癌）在全球范围内常见，且预后往往较差。约五分之一的此类癌症在癌细胞表面表达一种名为HER2的蛋白。15年多以来，曲妥珠单抗（一种阻断HER2的药物）联合化疗一直是这些患者的标准治疗。扎尼达单抗是一种新型治疗药物，其作用机制是同时结合两个相邻HER2蛋白上的两个不同部位，将二者并排连接。这可能比曲妥珠单抗更有效地阻断癌症生长。一项名为HERIZON-GEA-01的大型临床试验，在HER2阳性、起源于食管、胃或胃食管连接处的转移性癌症患者中，将扎尼达单抗联合化疗（联合或不联合另一种免疫系统药物替雷利珠单抗）与标准化疗方案曲妥珠单抗联合化疗进行头对头比较，作为一线治疗。该试验显示，接受扎尼达单抗联合化疗（联合或不联合免疫治疗）的患者生存期显著长于接受标准曲妥珠单抗联合化疗的患者。副作用总体可控，与曲妥珠单抗相比最显著的额外副作用为腹泻。基于这些结果，FDA于2026年8月批准了两种以扎尼达单抗为基础的联合方案作为新的一线治疗选择，取代曲妥珠单抗成为该 癌症类型。
完整摘要 · 英文原文
Esophagogastric cancer (EGC) remains a leading cause of cancer‑related mortality worldwide. Approximately 15-20% of advanced EGC overexpress human epidermal growth factor receptor 2 (HER2). Since 2010, trastuzumab in combination with platinum and fluoropyrimidine chemotherapy has been the cornerstone of first-line therapy for HER2-positive advanced EGC, with a modest overall survival benefit. The addition of pembrolizumab to trastuzumab and chemotherapy in the KEYNOTE-811 trial has improved outcomes in PD-L1‑positive tumors. Despite these advances, median overall survival remains below 20 months. Zanidatamab is a novel biparatopic HER2-directed antibody, designed to bind to two distinct extracellular domains of HER2, promoting receptor clustering, enhanced internalization, and immune-mediated cytotoxicity. This Drug Evaluation reviews the pharmacology, pharmacokinetics, clinical development, efficacy, safety, and regulatory status of zanidatamab in HER2-positive EGC. The phase III HERIZON-GEA-01 trial evaluated zanidatamab (with or without tislelizumab) plus chemotherapy as first-line treatment for HER2-positive advanced EGC. This trial demonstrated clinically meaningful improvements in progression-free and overall survival versus trastuzumab-based therapy, leading to FDA approval of zanidatamab plus chemotherapy, with or without tislelizumab, as first‑line treatment for HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma. Key questions remain regarding optimal patient selection, the role of tislelizumab across PD-L1 subgroups, sequencing with antibody-drug conjugates, and long-term safety. Cancers of the esophagus, stomach, and the junction between the stomach and the food pipe, known as esophagogastric cancer, are common globally and often have poor outcomes. About one in five of these cancers has a protein called HER2 on the surface of cancer cells. For over 15 years, trastuzumab, a drug that blocks HER2, when given with chemotherapy, has been the standard treatment for these patients. Zanidatamab is a new treatment that works by attaching to two different parts of two neighboring HER2 proteins at the same time by linking them side-by-side. This may block cancer growth more effectively than trastuzumab. A large clinical trial called HERIZON-GEA-01 tested zanidatamab combined with chemotherapy, with or without another immune system drug called tislelizumab, against standard trastuzumab plus chemotherapy as the first treatment for patients with HER2-positive spread cancer that started in the esophagus, stomach, or the junction between the stomach and the food pipe. This trial showed that patients receiving zanidatamab and chemotherapy with or without immunotherapy lived significantly longer than those receiving standard trastuzumab plus chemotherapy. Side effects were generally manageable, with diarrhea being the most notable additional side effect compared to trastuzumab. Based on these results, the FDA approved both zanidatamab-based combinations in August 2026 as a new first-line treatment option, replacing trastuzumab as the preferred HER2-targeted treatment for this type of cancer.