Gastric Cancer ( IF 7.4 ) Pub Date : 2021-05-16 , DOI: 10.1007/s10120-021-01196-3 Kohei Shitara 1 , Eishi Baba 2 , Kazumasa Fujitani 3 , Eiji Oki 4 , Satoshi Fujii 5 , Kensei Yamaguchi 6
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.
中文翻译:
曲妥珠单抗 deruxtecan 的发现和开发以及 HER2 阳性胃癌患者的安全管理
大约 12-15% 的胃癌 (GC) 为人表皮生长因子受体 2 (HER2) 阳性(HER2 免疫组织化学 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与化疗联合使用是 HER2 阳性 GC 的标准治疗方法,但其他 HER2 靶向疗法尽管在 HER2 阳性乳腺癌患者中显示出疗效,但尚未证明对 GC 患者具有生存获益。 。这表明使用目前可用的 HER2 靶向疗法治疗 HER2 阳性 GC 存在独特的挑战。Trastuzumab deruxtecan (T-DXd) 是一种抗体-药物偶联物,由抗 HER2 人单克隆 IgG1 抗体(其氨基酸序列与曲妥珠单抗相同)(一种酶促裂解的基于肽的接头)和 DXd(一种新型拓扑异构酶 I 抑制剂)组成。它释放的有效负载。T-DXd 具有较高的药物抗体比(约 8)和已证实的旁观者抗肿瘤作用。与标准疗法相比,它显示出显着的疗效,并在日本被批准作为 HER2 阳性 GC 的三线或后期治疗,在美国被批准作为二线或后期治疗。T-DXd 治疗与胃肠道和血液学不良事件以及间质性肺疾病 (ILD) 风险相关,日本的 ILD 风险高于日本以外的国家。然而,大多数不良事件,包括 ILD,可以通过主动监测和 T-DXd 剂量调整以及开始适当的治疗来控制。在这篇综述中,我们总结了 T-DXd 的发现和发展,并为 HER2 阳性 GC 患者的 T-DXd 安全管理(包括 ILD 监测)提供指导。