单剂迪瓦拉西布 (GDC-6036) 在具有KRAS G12C突变的固体瘤中
Adrian Sacher1, Patricia LoRusso1, Manish R Patel1
1From the Princess Margaret Cancer Centre, University Health Network, and the Departments of Medicine and Immunology, University of Toronto, Toronto (A. Sacher), and the Lady Davis Institute and the Segal Cancer Center, Jewish General Hospital, McGill University, Montreal (W.H.M.); Yale Cancer Center, Yale University, New Haven, CT (P.L.); Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota (M.R.P.); Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona (E.G.), Hospital Universitario Virgen del Rocio, Seville (A.F.), and Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc (L.P.-A.), and START MADRID-CIOCC, Hospital Universitario HM Sanchinarro (M.M.), Madrid - all in Spain; the UCL Cancer Institute, University College London Hospitals NHS Trust, London (M.D.F.), and the Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester and Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester (M.G.K.) - both in the United Kingdom; IRCCS Humanitas Research Center, Humanitas Cancer Center, and the Department of Biomedical Sciences, Humanitas University, Milan (A. Santoro); Asan Medical Center (T.W.K.), Seoul National University Hospital and Seoul National University Cancer Research Institute (S.-W.H.), and Seoul National University Bundang Hospital (J.-S.L.) - all in Seoul, South Korea; Linear Clinical Research, Perth, WA (S.B.), and the Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC (J.D.) - all in Australia; Dana-Farber Cancer Institute and Harvard Medical School - both in Boston (M.L.C.); Memorial Sloan Kettering Cancer Center, New York (K.A.); and City of Hope, Duarte (E.M.), and Genentech, South San Francisco (Y.C., Z.S., S.M., M.T.L., S.R.-J., J.C., N.V.D., J.L.S.) - both in California.
迪瓦拉西布在KRAS G12C突变癌症患者中显示出持久的临床反应,包括非小细胞肺癌和结直肠癌. 这种共价KRAS G12C抑制剂在1期研究中耐受性良好,并具有可管理的不良事件.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 临床药理学 临床药理学
背景情况:
- 迪瓦拉西布 (GDC-6036) 是一种强效和选择性的共价抑制剂,向KRAS G12C突变.
- 在各种固体瘤中,KRAS G12C突变很普遍,导致瘤发生.
研究的目的:
- 评估divarasib的安全性,药理动力学和抗瘤活性在患有KRAS G12C突变的高级固体瘤的患者中.
- 为了确定对divarasib治疗的反应和耐药性的生物标志物.
主要方法:
- 一个第1期,开放标签,口服二华的剂量升级研究 (50-400毫克每天一次).
- 137名患有晚期或转移性固体瘤 (NSCLC,结肠直肠癌,其他) 的患者被纳入.
- 评估了安全性,药理动力学,抗瘤反应 (RECIST标准) 和循环瘤DNA (ctDNA).
主要成果:
- 迪瓦拉西布一般耐受良好;没有发生剂量限制性毒性或与治疗相关的死亡.
- 在NSCLC中,确定的应答率为53.4%,在结直肠癌患者中为29.1%.
- 无进展存活时间的中位数为NSCLC的13.1个月和结直肠癌的5.6个月;ctDNA分析揭示了目标参与和抵抗机制.
结论:
- 迪瓦拉西布在KRAS G12C阳性固体瘤患者中显示出持久的临床反应.
- 这种药物表现出可控的安全性概况,主要是低级的不良事件.
- 生物标志物分析提供了对治疗反应和耐药性途径的见解.
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