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Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with
Joshua K Sabari1, Vamsidhar Velcheti1, Kazuhide Shimizu2,3
1Laura and Isaac Perlmutter Cancer Center, NYU Langone, New York, New York.
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 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 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. See related commentary by Kommalapati and Mansfield, p. 3179.
Insights
Adagrasib effectively targets KRASG12C-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM). This KRASG12C inhibitor shows promising CNS penetration and antitumor activity in preclinical models and early clinical data.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) presents a significant clinical challenge with poor prognosis.
- Adagrasib is an optimized small-molecule inhibitor targeting KRASG12C, designed for favorable pharmacokinetics and CNS penetration.
Purpose of the Study:
- To evaluate the propensity of KRAS-mutant NSCLC to develop BM.
- To characterize the preclinical and preliminary clinical antitumor activity of adagrasib in the context of BM.
Main Methods:
- Retrospective analysis of NSCLC patients to assess BM development.
- Preclinical studies in mice with intracranial KRASG12C-mutant NSCLC xenografts treated with adagrasib.
- Pharmacokinetic assessment of adagrasib in plasma, CSF, and brain.
- Evaluation of preliminary clinical data from two NSCLC patients with untreated BM receiving adagrasib.
Main Results:
- KRAS-mutant NSCLC showed a high propensity (≥40%) for developing BM.
- Adagrasib demonstrated CNS penetration, reaching concentrations above target IC50 in CSF.
- Preclinical models showed tumor regression and extended survival; preliminary clinical data indicated BM regression in treated patients.
Conclusions:
- Adagrasib exhibits promising activity against KRASG12C-mutant NSCLC with BM.
- Further clinical development of adagrasib is warranted for patients with untreated BM.
