ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers, 3 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
88 citing papers in PubMed, 3 syntheses or guidelines pooled it, 119 citations in OpenAlex.
- KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors.Journal of translational medicine · 2025Pooled it
- Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review.Frontiers in immunology · 2025Pooled it
- Progress and prospects of targeted therapy and immunotherapy for urachal carcinoma.Frontiers in pharmacology · 2023Pooled it
- Review
- Brain metastasis: Opportunities for novel therapies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel, CNS-Penetrant KRAS G12C Inhibitor.Journal of medicinal chemistry · 2026Article
- KRAS G12C-Targeted Therapy in Non-Small Cell Lung Cancer: From Resistant Salvage to Potential First-Line Backbone.International journal of molecular sciences · 2026Review
- [(Bromomethyl)phenyl]methyl-Conjugated Chalcone Derivatives as Potential Lung Cancer Inhibitors: Structure Modification, Molecular Docking, Molecular Dynamics and In Vitro Validation.International journal of molecular sciences · 2026Article
- The clinicopathologic characteristics and outcomes of uncommon KRAS mutations in patients with non-small cell lung cancer.Virchows Archiv : an international journal of pathology · 2026Article
- Survival of lung cancer patients with central nervous system metastases: from clinical trials to mouse models.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Article
- Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model.Nature communications · 2026Article
- RAS Inhibitors: Changing the Paradigm from the Undruggable.Pharmaceutics · 2026Review
- Radiosensitization of Glioblastoma by the K-ras Inhibitor RMC-6236.bioRxiv : the preprint server for biology · 2026Article
- Study of the blood-brain barrier-penetrating KRAS G12C inhibitor JMKX1899 in KRAS G12C-mutated NSCLC with brain metastases.Journal of the National Cancer Center · 2026Article
- Towards precision medicine for brain arteriovenous malformations.The Journal of clinical investigation · 2026Review
- Evaluating the efficacy of G12C inhibitors in conjunction with Gamma Knife radiosurgery for KRAS-mutant non-small cell lung cancer brain metastases.Journal of neuro-oncology · 2026Article
- SUNRAY-01 trial protocol: an innovative study design of olomorasib and pembrolizumab with or without chemotherapy inFuture oncology (London, England) · 2026Article
- Therapeutic advances with KRASCancer gene therapy · 2026Review
- Clinicopathological characteristics and prognosis of brain metastasis in non-small cell lung cancer: A retrospective study.Medicine · 2026Article
- Review
28 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
Abstract
purposePatients 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
designA 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.
resultsPatients 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.
conclusionsThese data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.