KRYSTAL-1试验：Adagrasib在未经治疗的中枢神经系统转移KRASG12C突变非小细胞肺癌患者中的颅内疗效

SCI

20 July 2023

Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRASG12C-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases

(JCO, IF: 50.717)

Negrao Marcelo V,Spira Alexander I,Heist Rebecca S et al. Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRASG12C-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases.[J] .J Clin Oncol, 2023, undefined: JCO2300046.

Patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without KRAS mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with KRASG12C-mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), in which adagrasib 600 mg was administered orally, twice daily. Study outcomes included the safety and clinical activity (intracranial [IC] and systemic) by blinded independent central review. Twenty-five patients with KRASG12C-mutated NSCLC and untreated CNS metastases were enrolled and evaluated (median follow-up, 13.7 months); 19 patients were radiographically evaluable for IC activity. Safety was consistent with previous reports of adagrasib, with grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months. Adagrasib is the first KRASG12C inhibitor to prospectively demonstrate IC activity in patients with KRASG12C-mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.

KRAS突变和未经治疗的中枢神经系统转移的非小细胞肺癌(NSCLC)患者预后比没有KRAS突变的类似患者差。Adagrasi在临床前试验里表现出中枢神经系统穿透性，在临床中表现出脑脊液穿透性。我们评估了KRYSTAL-1试验中未经治疗的中枢神经系统转移KRASG12C突变非小细胞肺癌患者Adagrasi的应用(ClinicalTrials.gov识别号：NCT03785249；Ib期队列)，其中口服Adagrasi 600 mg，每日两次。通过盲法独立中心评价，研究结果包括安全性和临床活性颅内和全身。25例未经治疗的中枢神经系统转移KRASG12C突变的非小细胞肺癌患者入组并进行评估(中位随访，13.7个月)；19例患者在影像学上可评估颅内活性。安全性与先前的Adagrasi报告一致，10名患者(40%)出现3级治疗相关不良事件，1名患者(4%)出现4级不良事件，无5级不良事件。最常见的中枢神经系统特异性不良事件包括语言障碍(24%)和头晕(20%)。Adagrasi的颅内客观缓解率为42%，疾病控制率为90%，无进展生存期为5.4个月，中位总生存期为11.4个月。Adagrasi是第一个KRASG12C抑制剂，在未经治疗的中枢神经系统转移KRASG12C突变非小细胞肺癌患者中前瞻性地显示出颅内活性，支持在该人群中的进一步研究。

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