Activity of Adagrasib (MRTX849) in Brain Metastases : Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer
©2022 The Authors; Published by the American Association for Cancer Research..
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.
| Errataetall: |
CommentIn: Clin Cancer Res. 2022 Aug 2;28(15):3179-3181. - PMID 35608481 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 28(2022), 15 vom: 02. Aug., Seite 3318-3328 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sabari, Joshua K [VerfasserIn] |
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| Links: |
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| Themen: |
8EOO6HQF8Y |
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| Anmerkungen: |
Date Completed 04.08.2022 Date Revised 10.07.2023 published: Print ClinicalTrials.gov: NCT03785249 CommentIn: Clin Cancer Res. 2022 Aug 2;28(15):3179-3181. - PMID 35608481 Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-22-0383 |
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| 100 | 1 | |a Sabari, Joshua K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Activity of Adagrasib (MRTX849) in Brain Metastases |b Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer |
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| 500 | |a Date Completed 04.08.2022 | ||
| 500 | |a Date Revised 10.07.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT03785249 | ||
| 500 | |a CommentIn: Clin Cancer Res. 2022 Aug 2;28(15):3179-3181. - PMID 35608481 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2022 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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