Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.
Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-22-0383
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发表时间：
2022-08-02
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KRAS突变型非小细胞肺癌（NSCLC）伴脑转移（BM）的患者预后不良。Adagrasib（MRTX 849）是一种有效的口服小分子KRASG 12 C抑制剂，可不可逆地选择性结合KRASG 12 C，将其锁定在非活性状态。Adagrasib已被优化以获得有利的药代动力学特性，包括长半衰期（> 24小时）、广泛的组织分布、剂量依赖性药代动力学和中枢神经系统渗透;然而，KRASG 12 C抑制剂的BM特异性抗肿瘤活性仍有待充分表征。回顾性数据库查询确定了KRAS突变型NSCLC患者，以了解其发生BM的倾向。临床前研究评估了adagrasib的理化和药代动力学特性。对携带颅内KRASG 12 C突变型NSCLC异种移植物（LU 99-Luc/H23-Luc/LU 65-Luc）的小鼠给予临床相关剂量的adagrasib，并测定血浆、脑脊液（CSF）和脑中adagrasib的水平沿着抗肿瘤活性。从KRYSTAL-1试验Ib期队列中接受adagrasib 600 mg每日两次治疗的2例BM未经治疗的NSCLC患者中收集初步临床数据;采集CSF，测量adagrasib浓度，并评价BM中的抗肿瘤活性。KRAS突变型NSCLC患者表现出发生BM的高倾向性（≥40%）。Adagrasib渗透到CSF中，并在多个临床前BM模型中证明了肿瘤消退和生存期延长。在2例未经治疗的BM NSCLC患者中，测得的adagrasib CSF浓度高于目标细胞IC 50。两例患者均表现出相应的BM消退，支持adagrasib在大脑中的潜在临床活性。这些数据支持进一步开发adagrasib用于KRASG 12 C突变型NSCLC伴未治疗BM患者。 参见Kommalapati和曼斯菲尔德的相关评论，第3179页
Patients with KRAS-mutant non–small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179