Divarasib（GDC-6036）是一种共价结合的KRAS G12C抑制剂，设计用于具有高效力和选择性。在一项1期研究中，我们评估了口服每日一次的divarasib（剂量范围从50到400毫克）用于携带KRAS G12C突变的晚期或转移性实体肿瘤患者。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和响应与耐药的生物标志物。共有137名患者（非小细胞肺癌60例，结直肠癌55例，其他实体肿瘤22例）接受了divarasib治疗。没有报道剂量限制性毒性效应或与治疗相关的死亡。治疗相关不良事件发生在127名患者中（93%）；15名患者（11%）出现3级不良事件，1名患者（1%）出现4级不良事件。治疗相关不良事件导致19名患者（14%）剂量减少，4名患者（3%）停止治疗。在非小细胞肺癌患者中，有53.4%的患者（95%置信区间[CI]，39.9%至66.7%）出现确认的疗效，并且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，有29.1%的患者（95% CI，17.6%至42.9%）出现确认的疗效，并且中位无进展生存期为5.6个月（95% CI，4.1%至8.2%）。其他实体肿瘤患者也观察到了疗效。循环肿瘤DNA的连续评估显示，与反应相关的KRAS G12C突变等位基因频率下降，并确定可能导致对divarasib耐药的基因组变化。divarasib治疗在KRAS G12C阳性肿瘤中产生持久的临床反应，且大多数不良事件为低级别。（由Genentech资助；ClinicalTrials.gov编号，NCT04449874.）版权所有 © 2023 Massachusetts Medical Society.

Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.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 KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed.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 KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib.Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).Copyright © 2023 Massachusetts Medical Society.