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Purpose: 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 (PK) properties, including long half-life (~24 hours), extensive tissue distribution, dose-dependent PK, and central nervous system penetration, however BM-specific anti-tumor activity of KRASG12C inhibitors remains to be fully characterized. Experimental Design: A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and PK 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 anti-tumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg BID in the Phase 1b cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and anti-tumor activity in BM evaluated. Results: Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM ({greater than or equal to}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. Conclusions: These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM.

clinical cancer research

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non–Small Cell Lung Cancer