单一化疗药剂Divarasib (GDC-6036) 在KRAS G12C突变实性肿瘤中的作用

SCI

31 August 2023

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation

（The New England journal of medicine；IF：158.5）

Sacher A, LoRusso P, Patel MR, Miller WH Jr, Garralda E, Forster MD, Santoro A, Falcon A, Kim TW, Paz-Ares L, Bowyer S, de Miguel M, Han SW, Krebs MG, Lee JS, Cheng ML, Arbour K, Massarelli E, Choi Y, Shi Z, Mandlekar S, Lin MT, Royer-Joo S, Chang J, Dharia NV, Schutzman JL, Desai J; GO42144 Investigator and Study Group. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRASG12C Mutation. N Engl J Med. 2023 Aug 24;389(8):710-721. doi: 10.1056/NEJMoa2303810. PMID: 37611121.

Corresponding authors: 

Dr. Sacher 

Princess Margaret Cancer Centre, 610 University Ave., Toronto, ON M5G 2M9, Canada.

adrian.sacher@uhn.ca 

Dr. Desai

Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne, VIC 3000, Australia. 

jayesh .desai@petermac.org

BACKGROUND 背景

Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. 

Divarasib（GDC-6036）是一种共价KRAS G12C抑制剂，其设计目的是具有高效能和高选择性。

METHODS 方法

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 bio-markers of response and resistance were also assessed.

在一项1期研究中，我们评估了每日一次口服divarasib（剂量范围从50mg到400mg）在带有KRAS G12C突变的晚期或转移性实性肿瘤患者中的应用。主要目的是评估安全性；也评估了药物代谢动力学、由研究者评估的抗肿瘤活性，以及其反应和耐药性的生物标志物。

RESULTS 结果

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. 

共有137名患者（60名非小细胞肺癌 [NSCLC] 患者，55名结直肠癌患者，22名其他实性肿瘤患者）接受了divarasib治疗。没有报告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（93%）中；15名患者（11%）出现3级事件，1名患者（1%）出现4级事件。治疗相关不良事件导致19名患者（14%）剂量减少，4名患者（3%）中止治疗。在NSCLC患者中，53.4%的患者（95%置信区间[CI]，39.9% 至66.7%）观察到确认缓解，中位无进展生存期为13.1个月（95% CI，8.8个月至无法估计）。在结直肠癌患者中，29.1%的患者（95% CI，17.6% 至42.9%）观察到确认缓解，中位无进展生存期为5.6个月（95% CI，4.1至8.2个月）。其他实性肿瘤患者也观察到了反应。循环肿瘤DNA的定期评估显示，与缓解相关的KRAS G12C变异等位基因频率下降，并确定了可能导致对divarasib耐药的基因组改变。

CONCLUSIONS 结论

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.) 

divarasib治疗使KRAS G12C阳性肿瘤得到了持久临床缓解，且伴随的主要是低级别的不良事件。（由Genentech资助；ClinicalTrials.gov编号，NCT04449874。）

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