Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Gastric Cancer. 2021 Jul;24(4):780-789. doi: 10.1007/s10120-021-01196-3. Epub 2021 May 16.
Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.
大约 12-15%的胃癌（GC）是人表皮生长因子受体-2（HER2）阳性（HER2 免疫组化 3+或 2+/原位杂交+[ERBB2/CEP17≥2.0]）。虽然抗 HER2 单克隆抗体曲妥珠单抗联合化疗是 HER2 阳性 GC 的标准治疗方法，但其他 HER2 靶向治疗在 GC 患者中并未显示出生存获益，尽管在 HER2 阳性乳腺癌患者中显示出疗效。这表明，目前可用的 HER2 靶向治疗在治疗 HER2 阳性 GC 方面存在独特的挑战。曲妥珠单抗 deruxtecan（T-DXd）是一种抗体药物偶联物，由与曲妥珠单抗具有相同氨基酸序列的抗 HER2 人源单克隆 IgG1 抗体、可酶切的基于肽的接头、以及作为其释放有效载荷的新型拓扑异构酶 I 抑制剂 DXd 组成。T-DXd 具有高药物抗体比（约 8）和证明的旁观者抗肿瘤作用。与标准疗法相比，它显示出显著的疗效，并在日本被批准用于 HER2 阳性 GC 的三线或更后线治疗，在美国被批准用于二线或更后线治疗。T-DXd 治疗与胃肠道和血液学不良事件以及间质性肺病（ILD）风险相关，ILD 风险在日本高于日本以外的其他国家。然而，大多数不良事件，包括 ILD，可以通过主动监测和 T-DXd 剂量调整以及充分治疗来管理。在这篇综述中，我们总结了 T-DXd 的发现和开发，并为 HER2 阳性 GC 患者的 T-DXd 安全性管理，包括 ILD 监测，提供了指导。
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