Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer
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 favorab...
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| Veröffentlicht in: | Clinical cancer research 2022-08, Vol.28 (15), p.3318-3328 |
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| creator | Sabari, Joshua K Velcheti, Vamsidhar Shimizu, Kazuhide Strickland, Matthew R Heist, Rebecca S Singh, Mohini Nayyar, Naema Giobbie-Hurder, Anita Digumarthy, Subba R Gainor, Justin F Rajan, Anant P Nieblas-Bedolla, Edwin Burns, Aaron C Hallin, Jill Olson, Peter Christensen, James G Kurz, Sylvia C Brastianos, Priscilla K Wakimoto, Hiroaki |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1158/1078-0432.CCR-22-0383 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-22-0383</identifier><identifier>PMID: 35404402</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Acetonitriles ; Animals ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - mortality ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - pathology ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Mice ; Piperazines ; Proto-Oncogene Proteins p21(ras) - genetics ; Pyrimidines ; Retrospective Studies ; Translational Cancer Mechanisms and Therapy</subject><ispartof>Clinical cancer research, 2022-08, Vol.28 (15), p.3318-3328</ispartof><rights>2022 The Authors; Published by the American Association for Cancer Research.</rights><rights>2022 The Authors; Published by the American Association for Cancer Research 2022 American Association for Cancer Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-192536c4f8258d7a1a72e662a9e3d7b07d22a06d9970a6d9dd436f1c58fb24173</citedby><cites>FETCH-LOGICAL-c463t-192536c4f8258d7a1a72e662a9e3d7b07d22a06d9970a6d9dd436f1c58fb24173</cites><orcidid>0000-0003-4470-8425 ; 0000-0003-2496-7737 ; 0000-0001-5879-1800 ; 0000-0001-8225-241X ; 0000-0002-5247-5636 ; 0000-0001-9056-2477 ; 0000-0002-1556-1543 ; 0000-0001-9485-3781 ; 0000-0003-4041-6716 ; 0000-0001-7845-0712 ; 0000-0001-8697-4081 ; 0000-0002-6589-0759 ; 0000-0002-8443-7116</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35404402$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sabari, Joshua K</creatorcontrib><creatorcontrib>Velcheti, Vamsidhar</creatorcontrib><creatorcontrib>Shimizu, Kazuhide</creatorcontrib><creatorcontrib>Strickland, Matthew R</creatorcontrib><creatorcontrib>Heist, Rebecca S</creatorcontrib><creatorcontrib>Singh, Mohini</creatorcontrib><creatorcontrib>Nayyar, Naema</creatorcontrib><creatorcontrib>Giobbie-Hurder, Anita</creatorcontrib><creatorcontrib>Digumarthy, Subba R</creatorcontrib><creatorcontrib>Gainor, Justin F</creatorcontrib><creatorcontrib>Rajan, Anant P</creatorcontrib><creatorcontrib>Nieblas-Bedolla, Edwin</creatorcontrib><creatorcontrib>Burns, Aaron C</creatorcontrib><creatorcontrib>Hallin, Jill</creatorcontrib><creatorcontrib>Olson, Peter</creatorcontrib><creatorcontrib>Christensen, James G</creatorcontrib><creatorcontrib>Kurz, Sylvia C</creatorcontrib><creatorcontrib>Brastianos, Priscilla K</creatorcontrib><creatorcontrib>Wakimoto, Hiroaki</creatorcontrib><title>Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>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.
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.
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.
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.</description><subject>Acetonitriles</subject><subject>Animals</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - mortality</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>Piperazines</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Pyrimidines</subject><subject>Retrospective Studies</subject><subject>Translational Cancer Mechanisms and Therapy</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkV1LXDEQhoO0-NX-hJZcthex-TwfvRC2x9aKu62sCr0Ls0nOGjmbI0nW4i_p320WXVEYZsLMvO8EHoQ-MHrEmGq-MFo3hErBj7puTjgnVDRiB-0zpWoieKXelPd2Zw8dpHRLKZOMyl20J5SkUlK-j_5NTPb3Pj_gsccTC8sIyS_wp9n86k8j28_YB_wtQskzlyGVcOkrvojODD54AwOejdYNCUOwuNv2TiAD7uO4wheQvQs54b8-3-Dz-eTylPGOzNYZQsa_xkAuVzAMuHMlTddhiTsIxsV36G0PQ3Lvn-ohuv7x_ar7Saa_T8-6yZQYWYlMWMuVqIzsG64aWwODmruq4tA6YesFrS3nQCvbtjWFUqyVouqZUU2_4JLV4hAdP_rerRcrZ035a4RB30W_gvigR_D69ST4G70c73VbrjQVLwbq0cDEMaXo-mcto3pDSm8o6A0FXUhpzvWGVNF9fHn4WbVFI_4DbTaPWg</recordid><startdate>20220802</startdate><enddate>20220802</enddate><creator>Sabari, Joshua K</creator><creator>Velcheti, Vamsidhar</creator><creator>Shimizu, Kazuhide</creator><creator>Strickland, Matthew R</creator><creator>Heist, Rebecca S</creator><creator>Singh, Mohini</creator><creator>Nayyar, Naema</creator><creator>Giobbie-Hurder, Anita</creator><creator>Digumarthy, Subba R</creator><creator>Gainor, Justin F</creator><creator>Rajan, Anant P</creator><creator>Nieblas-Bedolla, Edwin</creator><creator>Burns, Aaron C</creator><creator>Hallin, Jill</creator><creator>Olson, Peter</creator><creator>Christensen, James G</creator><creator>Kurz, Sylvia C</creator><creator>Brastianos, Priscilla K</creator><creator>Wakimoto, Hiroaki</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4470-8425</orcidid><orcidid>https://orcid.org/0000-0003-2496-7737</orcidid><orcidid>https://orcid.org/0000-0001-5879-1800</orcidid><orcidid>https://orcid.org/0000-0001-8225-241X</orcidid><orcidid>https://orcid.org/0000-0002-5247-5636</orcidid><orcidid>https://orcid.org/0000-0001-9056-2477</orcidid><orcidid>https://orcid.org/0000-0002-1556-1543</orcidid><orcidid>https://orcid.org/0000-0001-9485-3781</orcidid><orcidid>https://orcid.org/0000-0003-4041-6716</orcidid><orcidid>https://orcid.org/0000-0001-7845-0712</orcidid><orcidid>https://orcid.org/0000-0001-8697-4081</orcidid><orcidid>https://orcid.org/0000-0002-6589-0759</orcidid><orcidid>https://orcid.org/0000-0002-8443-7116</orcidid></search><sort><creationdate>20220802</creationdate><title>Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer</title><author>Sabari, Joshua K ; Velcheti, Vamsidhar ; Shimizu, Kazuhide ; Strickland, Matthew R ; Heist, Rebecca S ; Singh, Mohini ; Nayyar, Naema ; Giobbie-Hurder, Anita ; Digumarthy, Subba R ; Gainor, Justin F ; Rajan, Anant P ; Nieblas-Bedolla, Edwin ; Burns, Aaron C ; Hallin, Jill ; Olson, Peter ; Christensen, James G ; Kurz, Sylvia C ; Brastianos, Priscilla K ; Wakimoto, Hiroaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-192536c4f8258d7a1a72e662a9e3d7b07d22a06d9970a6d9dd436f1c58fb24173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Acetonitriles</topic><topic>Animals</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - mortality</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - pathology</topic><topic>Mice</topic><topic>Piperazines</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Pyrimidines</topic><topic>Retrospective Studies</topic><topic>Translational Cancer Mechanisms and Therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sabari, Joshua K</creatorcontrib><creatorcontrib>Velcheti, Vamsidhar</creatorcontrib><creatorcontrib>Shimizu, Kazuhide</creatorcontrib><creatorcontrib>Strickland, Matthew R</creatorcontrib><creatorcontrib>Heist, Rebecca S</creatorcontrib><creatorcontrib>Singh, Mohini</creatorcontrib><creatorcontrib>Nayyar, Naema</creatorcontrib><creatorcontrib>Giobbie-Hurder, Anita</creatorcontrib><creatorcontrib>Digumarthy, Subba R</creatorcontrib><creatorcontrib>Gainor, Justin F</creatorcontrib><creatorcontrib>Rajan, Anant P</creatorcontrib><creatorcontrib>Nieblas-Bedolla, Edwin</creatorcontrib><creatorcontrib>Burns, Aaron C</creatorcontrib><creatorcontrib>Hallin, Jill</creatorcontrib><creatorcontrib>Olson, Peter</creatorcontrib><creatorcontrib>Christensen, James G</creatorcontrib><creatorcontrib>Kurz, Sylvia C</creatorcontrib><creatorcontrib>Brastianos, Priscilla K</creatorcontrib><creatorcontrib>Wakimoto, Hiroaki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sabari, Joshua K</au><au>Velcheti, Vamsidhar</au><au>Shimizu, Kazuhide</au><au>Strickland, Matthew R</au><au>Heist, Rebecca S</au><au>Singh, Mohini</au><au>Nayyar, Naema</au><au>Giobbie-Hurder, Anita</au><au>Digumarthy, Subba R</au><au>Gainor, Justin F</au><au>Rajan, Anant P</au><au>Nieblas-Bedolla, Edwin</au><au>Burns, Aaron C</au><au>Hallin, Jill</au><au>Olson, Peter</au><au>Christensen, James G</au><au>Kurz, Sylvia C</au><au>Brastianos, Priscilla K</au><au>Wakimoto, Hiroaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2022-08-02</date><risdate>2022</risdate><volume>28</volume><issue>15</issue><spage>3318</spage><epage>3328</epage><pages>3318-3328</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>35404402</pmid><doi>10.1158/1078-0432.CCR-22-0383</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4470-8425</orcidid><orcidid>https://orcid.org/0000-0003-2496-7737</orcidid><orcidid>https://orcid.org/0000-0001-5879-1800</orcidid><orcidid>https://orcid.org/0000-0001-8225-241X</orcidid><orcidid>https://orcid.org/0000-0002-5247-5636</orcidid><orcidid>https://orcid.org/0000-0001-9056-2477</orcidid><orcidid>https://orcid.org/0000-0002-1556-1543</orcidid><orcidid>https://orcid.org/0000-0001-9485-3781</orcidid><orcidid>https://orcid.org/0000-0003-4041-6716</orcidid><orcidid>https://orcid.org/0000-0001-7845-0712</orcidid><orcidid>https://orcid.org/0000-0001-8697-4081</orcidid><orcidid>https://orcid.org/0000-0002-6589-0759</orcidid><orcidid>https://orcid.org/0000-0002-8443-7116</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acetonitriles Animals Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - mortality Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - pathology Mice Piperazines Proto-Oncogene Proteins p21(ras) - genetics Pyrimidines Retrospective Studies Translational Cancer Mechanisms and Therapy |
| title | Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer |
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