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曲妥珠单抗-deruxtecan治疗HER2阳性经治胃癌的研究
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer


Kohei Shitara ... 肿瘤 • 2020.06.18
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曲妥珠单抗偶联药治疗HER2阳性难治性胃癌,疗效远超标准三线疗法

 

周爱萍 

国家癌症中心/中国医学科学院肿瘤医院内科

 

晚期胃癌后线治疗手段十分有限,且疗效不理想,临床上存在未被满足的巨大需求,是目前胃癌治疗领域的难点。5月29日,与ASCO 2020年会同步发表于《新英格兰医学杂志》的名为DESTINY-Gastric01的临床试验1,为HER2阳性晚期胃癌治疗提供了新希望。

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摘要


背景

曲妥珠单抗-deruxtecan(DS-8201)是由抗HER2(人表皮生长因子受体2)抗体、可裂解的四肽连接子和细胞毒性拓扑异构酶Ⅰ抑制剂组成的抗体偶联药物。该药对HER2阳性晚期胃癌可能有效。

 

方法

在一项开放标签、随机、2期临床试验中,我们比较了曲妥珠单抗-deruxtecan与化疗对HER2阳性晚期胃癌患者的疗效。在既往至少两种方案(包括曲妥珠单抗)治疗期间出现疾病进展,并被集中确认为HER2阳性胃腺癌或胃食管结合部腺癌的患者被随机分组(2∶1的比例),分别接受曲妥珠单抗-deruxtecan(6.4 mg/kg,每3周1次)治疗或医师选择的化疗。主要终点是经独立集中审核判定的客观缓解率。次要终点包括总生存期、缓解持续时间、无进展生存期、经过确认的疾病缓解(缓解持续时间≥4周)和安全性。

 

结果

共计187例患者接受了治疗,其中125例接受了曲妥珠单抗-deruxtecan治疗,62例接受了化疗(55例接受了伊立替康治疗,7例接受了紫杉醇治疗)。曲妥珠单抗-deruxtecan组51%的患者达到了客观缓解,而医师选择化疗组为14%(P<0.001)。曲妥珠单抗-deruxtecan组的总生存期比化疗组长(中位数,12.5个月 vs. 8.4个月;死亡的风险比,0.59;95% CI,0.39~0.88;P=0.01,这一数值超过了O’Brien-Fleming法预设的界值[根据死亡人数计算为0.0202])。最常见的3级或更高级别不良事件包括中性粒细胞计数减少(曲妥珠单抗-deruxtecan组为51%,医师选择化疗组为24%)、贫血(分别为38%和23%)和白细胞计数减少(21%和11%)。经独立委员会裁定,共有12例患者出现与曲妥珠单抗-deruxtecan相关的间质性肺病或肺炎(9例患者为1或2级,3例为3或4级)。曲妥珠单抗-deruxtecan组发生了1例与药物相关的死亡事件(死于肺炎)。在医师选择化疗组未发生与药物相关的死亡事件。

 

结论

在HER2阳性胃癌患者中,与标准治疗相比,曲妥珠单抗-deruxtecan显著改善了患者的客观缓解率和总生存期。骨髓抑制和间质性肺病是需要关注的毒性反应(由日本第一三共株式会社资助,DESTINY-Gastric01在Clinical-Trials.gov注册号为NCT03329690)。





作者信息

Kohei Shitara, M.D., Yung-Jue Bang, M.D., Ph.D., Satoru Iwasa, M.D., Ph.D., Naotoshi Sugimoto, M.D., Ph.D., Min-Hee Ryu, M.D., Ph.D., Daisuke Sakai, M.D., Ph.D., Hyun-Cheol Chung, M.D., Ph.D., Hisato Kawakami, M.D., Ph.D., Hiroshi Yabusaki, M.D., Ph.D., Jeeyun Lee, M.D., Ph.D., Kaku Saito, M.Sc., Yoshinori Kawaguchi, M.Sc., Takahiro Kamio, M.D., Akihito Kojima, M.Sc., Masahiro Sugihara, Ph.D., and Kensei Yamaguchi, M.D. for the DESTINY-Gastric01 Investigators*
From the National Cancer Center Hospital East, Kashiwa (K. Shitara), the National Cancer Center Hospital (S.I.), Daiichi Sankyo (T.K., A.K., M.S.), and the Cancer Institute Hospital of JFCR (K.Y.), Tokyo, the Osaka International Cancer Institute (N.S.), Osaka University Hospital (D.S.), and Kindai University Hospital (H.K.), Osaka, and Niigata Cancer Center Hospital, Niigata (H.Y.) — all in Japan; Seoul National University College of Medicine (Y.-J.B.), the Asan Medical Center, University of Ulsan College of Medicine (M.-H.R.), the Yonsei Cancer Center, Yonsei University College of Medicine (H.-C.C.), and the Samsung Medical Center, Sungkyunkwan University School of Medicine (J.L.) — all in Seoul, South Korea; and Daiichi Sankyo, Basking Ridge, NJ (K. Saito, Y.K.). Address reprint requests to Dr. Shitara at the National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan, or at kshitara@east.ncc.go.jp. *A list of the DESTINY-Gastric01 Investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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