Intracranial Activity of Adagrasib in Patients With KRAS G12C–Mutated NSCLC and Untreated CNS Metastases

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In an analysis reported in the Journal of Clinical Oncology, Negrao et al identified outcomes in the KRYSTAL-1 trial among patients with advanced KRAS G12C–mutated non–small cell lung cancer (NSCLC) who had untreated central nervous system (CNS) metastases at baseline and were treated with adagrasib.

The KRYSTAL-1 trial supported the December 2022 accelerated approval of adagrasib in patients with KRAS G12C–mutated locally advanced or metastatic NSCLC.

Study Details

The trial included 25 patients with untreated CNS metastases (among 116 total patients) who received the study dose of adagrasib at 600 mg twice daily. Median follow-up among the 25 patients was 13.7 months (95% confidence interval [CI] = 8.5 months to not estimable).

Key Findings

A total of 19 patients were radiographically evaluable for intracranial activity. Intracranial objective response was observed in eight patients (42%, 95% CI = 20.3%–66.5%), with complete response in three. The disease control rate was 90%. Median duration of response was 12.7 months. Among all 25 patients, median intracranial progression-free survival was 5.4 months (95% CI = 2.7 months to not estimable), with a 12-month rate of 33.9%. Median overall survival was 11.4 months (95% CI = 5.5–14.9 months), with a 12-month rate of 41.1%.  

Among the 25 patients, grade 3 or 4 treatment-related adverse events occurred in 11 patients (44%; grade 4 in 1 patient), most commonly vomiting (16%), nausea (12%), and dizziness (12%). The most common CNS-specific treatment-related adverse events of any grade included dysgeusia (24%) and dizziness (20%). No treatment-related deaths occurred. 

Among the 25 patients, the systemic objective response rate was 30%, the median duration of response was 5.6 months, and systemic median progression-free survival was 5.3 months.

The investigators concluded, “Adagrasib is the first KRAS G12C inhibitor to prospectively demonstrate intracranial activity in patients with KRAS G12C–mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.”

Marcelo V. Negrao, MD, of the Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Mirati Therapeutics, Inc. For full disclosures of the study authors, visit

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