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

Abstract

Purpose: Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oralsmall-moleculeKRASG12C 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. Experimental Design: 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. Results: 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 preclinicalBMmodels. In 2 patients withNSCLCand untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated correspondingBMregression, 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.