单药迪瓦西布（GDC-6036）治疗携带G12C突变的实体瘤
Single-Agent Divarasib (GDC-6036) in Solid Tumors with a G12C Mutation.
作者信息
Sacher Adrian, LoRusso Patricia, Patel Manish R, Miller Wilson H, Garralda Elena, Forster Martin D, Santoro Armando, Falcon Alejandro, Kim Tae Won, Paz-Ares Luis, Bowyer Samantha, de Miguel Maria, Han Sae-Won, Krebs Matthew G, Lee Jong-Seok, Cheng Michael L, Arbour Kathryn, Massarelli Erminia, Choi Yoonha, Shi Zhen, Mandlekar Sandhya, Lin Mark T, Royer-Joo Stephanie, Chang Julie, Dharia Neekesh V, Schutzman Jennifer L, Desai Jayesh
机构信息
From 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.
出版信息
N Engl J Med. 2023 Aug 24;389(8):710-721. doi: 10.1056/NEJMoa2303810.
BACKGROUND
Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.
METHODS
In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed.
RESULTS
A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib.
CONCLUSIONS
Treatment with divarasib resulted in durable clinical responses across G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).
背景
迪瓦西布（GDC-6036）是一种共价KRAS G12C抑制剂，设计用于具有高效力和选择性。
方法
在一项1期研究中，我们评估了迪瓦西布在携带G12C突变的晚期或转移性实体瘤患者中每日口服一次（剂量范围为50至400毫克）的情况。主要目标是评估安全性；还评估了药代动力学、研究者评估的抗肿瘤活性以及反应和耐药性的生物标志物。
结果
共有137例患者（60例非小细胞肺癌[NSCLC]、55例结直肠癌和22例其他实体瘤）接受了迪瓦西布治疗。未报告剂量限制性毒性作用或与治疗相关的死亡。127例患者（93%）发生了与治疗相关的不良事件；3级事件发生在15例患者（11%），4级事件发生在1例患者（1%）。与治疗相关的不良事件导致19例患者（14%）剂量减少，4例患者（3%）停止治疗。在NSCLC患者中，53.4%的患者观察到确认的反应（95%置信区间[CI]，39.9至66.7），中位无进展生存期为13.1个月（95%CI，8.8至无法估计）。在结直肠癌患者中，29.1%的患者观察到确认的反应（95%CI，17.6至42.9），中位无进展生存期为5.6个月（95%CI，4.1至8.2）。在其他实体瘤患者中也观察到了反应。循环肿瘤DNA的系列评估显示，与反应相关的G12C变异等位基因频率下降，并确定了可能赋予对迪瓦西布耐药性的基因组改变。
结论
迪瓦西布治疗导致G12C阳性肿瘤产生持久的临床反应，不良事件大多为低级别。（由基因泰克资助；ClinicalTrials.gov编号，NCT04449874。）
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