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通过sotorasib抑制KRASG12C治疗晚期实体瘤
KRASG12C Inhibition in Advanced Solid Tumors


David S. Hong ... 肿瘤 • 2020.09.24
相关阅读
• 通过sotorasib抑制KRAS G12C治疗晚期实体瘤 • 追踪非小细胞肺癌的进化 • 晚期非小细胞肺癌的精确诊断和治疗 • 透过系统发生树了解癌症进化“森林”

通过sotorasib抑制KRASG12C治疗晚期实体瘤的首个1期研究结果喜人

 

梁乃新

北京协和医院胸外科

 

KRAS p.G12C突变发生于13%的非小细胞肺癌(NSCLC)以及1%~3%的结直肠癌和其他癌症。突变的KRAS蛋白一直被视为“不可成药”,原因是其对GTP的亲和力高且缺乏可利用的结合口袋。目前尚无任何靶向癌症KRAS突变的疗法通过审批。sotorasib是选择性、不可逆性靶向KRAS p.G12C的小分子,优化了与之前未被利用的一个表面凹槽之间的不可逆相互作用,使得效力和选择性得到增强,从而有可能解决携带KRAS p.G12C突变的肿瘤患者治疗难题。

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摘要


背景

目前尚无任何靶向癌症KRAS突变的疗法通过审批。KRAS p.G12C突变发生于13%的非小细胞肺癌(NSCLC)以及1%~3%的结直肠癌和其他癌症。sotorasib是选择性、不可逆性靶向KRASG12C的小分子。

 

方法

我们在携带KRAS p.G12C突变的晚期实体瘤患者中对sotorasib开展了一项1期试验。患者每日1次口服sotorasib。主要终点是安全性。关键次要终点包括药代动力学和根据《实体瘤疗效评价标准》(Response Evaluation Criteria in Solid TumorsRECIST)1.1版评估的客观缓解。

 

结果

共计129例患者(59例NSCLC患者、42例结直肠癌患者和28例其他肿瘤患者)被纳入了剂量递增和扩展队列。患者因转移性疾病接受过的抗癌治疗的线数中位数为3(范围,0~11)。本研究未观察到剂量限制性毒性作用或与治疗相关的死亡。共计73例患者(56.6%)发生了与治疗相关的不良事件;15例患者(11.6%)发生了3级或4级事件。在NSCLC患者亚组中,32.2%(19例患者)达到了经证实的客观缓解(完全或部分缓解),88.1%(52例患者)达到了疾病控制(客观缓解或疾病稳定);中位无进展生存期为6.3个月(范围,0.0+~14.9[+号表示数值包括在数据截止时删失的患者数据])。在结直肠癌患者亚组中,7.1%(3例患者)达到了经证实的缓解,73.8%(31例患者)达到了疾病控制;中位无进展生存期为4.0个月(范围,0.0+~11.1+)。在胰腺癌、子宫内膜癌、阑尾癌和黑色素瘤患者中也观察到了缓解。

 

结论

在既往接受过大量治疗,携带KRAS p.G12C突变的晚期实体瘤患者中,sotorasib表现出令人鼓舞的抗癌活性。11.6%的患者发生了与治疗相关的3级或4级毒性作用(由安进等资助,CodeBreaK100在ClinicalTrials.gov注册号为NCT03600883)。





作者信息

David S. Hong, M.D., Marwan G. Fakih, M.D., John H. Strickler, M.D., Jayesh Desai, M.D., Gregory A. Durm, M.D., Geoffrey I. Shapiro, M.D., Ph.D., Gerald S. Falchook, M.D., Timothy J. Price, M.B., B.S., D.Hlth.Sc., Adrian Sacher, M.D., M.M.Sc., Crystal S. Denlinger, M.D., Yung-Jue Bang, M.D., Ph.D., Grace K. Dy, M.D., John C. Krauss, M.D., Yasutoshi Kuboki, M.D., James C. Kuo, M.D., Andrew L. Coveler, M.D., Keunchil Park, M.D., Ph.D., Tae Won Kim, M.D., Ph.D., Fabrice Barlesi, M.D., Ph.D., Pamela N. Munster, M.D., Suresh S. Ramalingam, M.D., Timothy F. Burns, M.D., Ph.D., Funda Meric-Bernstam, M.D., Haby Henary, M.D., Jude Ngang, Pharm.D., Gataree Ngarmchamnanrith, M.D., June Kim, Ph.D., Brett E. Houk, Ph.D., Jude Canon, Ph.D., J. Russell Lipford, Ph.D., Gregory Friberg, M.D., Piro Lito, M.D., Ph.D., Ramaswamy Govindan, M.D., and Bob T. Li, M.D., M.P.H.
From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) — all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) — all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana–Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) — all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) — all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.). Address reprint requests to Dr. Hong at the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, or at dshong@mdanderson.org; or to Dr. Li at the Thoracic Oncology and Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY 10065, or at lib1@mskcc.org.

 

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