Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer
Purpose: Patients with KRAS-mutant non-small cell lung cancer (NSCLC) and brain metastases (BM) face a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule inhibitor of KRASG12C, irreversibly and selectively binds to KRASG12C, keeping it in an inactive state. Optimized for favorable pharmacokinetics, adagrasib has a long half-life (approximately 24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and the ability to penetrate the central nervous system. However, the specific antitumor activity of KRASG12C inhibitors in brain metastases has yet to be fully explored.
Experimental Design: A retrospective analysis identified patients with KRAS-mutant NSCLC to assess their likelihood of developing brain metastases. Preclinical studies evaluated the physicochemical and pharmacokinetic properties of adagrasib. Mice with intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant doses of adagrasib, and its levels in plasma, cerebrospinal fluid (CSF), and brain tissue were measured alongside its antitumor activity. Preliminary clinical data were gathered from two patients with NSCLC and untreated BM who received adagrasib at 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected for adagrasib concentration measurement, and antitumor activity in BM was evaluated.
Results: Patients with KRAS-mutant NSCLC showed a high propensity for developing brain metastases (≥40%). Adagrasib penetrated the CSF and demonstrated tumor regression and prolonged survival in several preclinical BM models. In the two patients with untreated BM, adagrasib concentrations in the CSF exceeded the target cellular IC50, and both patients showed corresponding regression of their brain metastases, indicating potential clinical efficacy.
Conclusions: These findings support the further development of adagrasib for patients with KRASG12C-mutant NSCLC and untreated brain metastases.