MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial
Abstract Homozygous MTAP deletion occurs in ~15% of cancers, making them vulnerable to decreases in the concentration of S-adenosylmethionine (SAM). AG-270/S095033 is an oral, potent, reversible inhibitor of methionine adenosyltransferase 2 A (MAT2A), the enzyme primarily responsible for the synthes...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55316-5 |
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| author | Mrinal Gounder Melissa Johnson Rebecca S. Heist Geoffrey I. Shapiro Sophie Postel-Vinay Frederick H. Wilson Elena Garralda Gerburg Wulf Caroline Almon Salah Nabhan Elia Aguado-Fraile Peng He Mathilde Romagnoli Mohammad Hossain Rohini Narayanaswamy Amel Sadou-Dubourgnoux Michael Cooper Vasileios Askoxylakis Howard A. Burris Josep Tabernero |
| author_facet | Mrinal Gounder Melissa Johnson Rebecca S. Heist Geoffrey I. Shapiro Sophie Postel-Vinay Frederick H. Wilson Elena Garralda Gerburg Wulf Caroline Almon Salah Nabhan Elia Aguado-Fraile Peng He Mathilde Romagnoli Mohammad Hossain Rohini Narayanaswamy Amel Sadou-Dubourgnoux Michael Cooper Vasileios Askoxylakis Howard A. Burris Josep Tabernero |
| author_sort | Mrinal Gounder |
| collection | DOAJ |
| description | Abstract Homozygous MTAP deletion occurs in ~15% of cancers, making them vulnerable to decreases in the concentration of S-adenosylmethionine (SAM). AG-270/S095033 is an oral, potent, reversible inhibitor of methionine adenosyltransferase 2 A (MAT2A), the enzyme primarily responsible for the synthesis of SAM. We report results from the first-in-human, phase 1 trial of AG-270/S095033 as monotherapy in patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03435250). Eligible patients had tumors with homozygous deletion of CDKN2A/MTAP and/or loss of MTAP protein by immunohistochemistry. Patients received AG-270/S095033 once daily (QD) or twice daily (BID) in 28-day cycles. The primary objective was to assess the maximum tolerated dose (MTD) of AG-270/S095033. Secondary objectives included safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile. Our data provide preliminary evidence of clinical activity and proof-of-mechanism for MAT2A inhibition. |
| format | Article |
| id | doaj-art-a3ec6067d9ff4bfc8e8a51ecab0d2f9c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-a3ec6067d9ff4bfc8e8a51ecab0d2f9c2025-01-12T12:30:42ZengNature PortfolioNature Communications2041-17232025-01-0116111110.1038/s41467-024-55316-5MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trialMrinal Gounder0Melissa Johnson1Rebecca S. Heist2Geoffrey I. Shapiro3Sophie Postel-Vinay4Frederick H. Wilson5Elena Garralda6Gerburg Wulf7Caroline Almon8Salah Nabhan9Elia Aguado-Fraile10Peng He11Mathilde Romagnoli12Mohammad Hossain13Rohini Narayanaswamy14Amel Sadou-Dubourgnoux15Michael Cooper16Vasileios Askoxylakis17Howard A. Burris18Josep Tabernero19Memorial Sloan Kettering Cancer Center; Weill Cornell Medical CollegeSarah Cannon Research InstituteMassachusetts General HospitalDana-Farber Cancer CenterInstitut Gustave Roussy and U981 INSERMYale Cancer CenterVall d’Hebron Institute of OncologyBeth Israel Deaconess Medical CenterAgios Pharmaceuticals Inc.Agios Pharmaceuticals Inc.Agios Pharmaceuticals Inc.ServierServierAgios Pharmaceuticals Inc.ServierServierAgios Pharmaceuticals Inc.ServierSarah Cannon Research InstituteVall d’Hebron Institute of OncologyAbstract Homozygous MTAP deletion occurs in ~15% of cancers, making them vulnerable to decreases in the concentration of S-adenosylmethionine (SAM). AG-270/S095033 is an oral, potent, reversible inhibitor of methionine adenosyltransferase 2 A (MAT2A), the enzyme primarily responsible for the synthesis of SAM. We report results from the first-in-human, phase 1 trial of AG-270/S095033 as monotherapy in patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03435250). Eligible patients had tumors with homozygous deletion of CDKN2A/MTAP and/or loss of MTAP protein by immunohistochemistry. Patients received AG-270/S095033 once daily (QD) or twice daily (BID) in 28-day cycles. The primary objective was to assess the maximum tolerated dose (MTD) of AG-270/S095033. Secondary objectives included safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile. Our data provide preliminary evidence of clinical activity and proof-of-mechanism for MAT2A inhibition.https://doi.org/10.1038/s41467-024-55316-5 |
| spellingShingle | Mrinal Gounder Melissa Johnson Rebecca S. Heist Geoffrey I. Shapiro Sophie Postel-Vinay Frederick H. Wilson Elena Garralda Gerburg Wulf Caroline Almon Salah Nabhan Elia Aguado-Fraile Peng He Mathilde Romagnoli Mohammad Hossain Rohini Narayanaswamy Amel Sadou-Dubourgnoux Michael Cooper Vasileios Askoxylakis Howard A. Burris Josep Tabernero MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial Nature Communications |
| title | MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial |
| title_full | MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial |
| title_fullStr | MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial |
| title_full_unstemmed | MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial |
| title_short | MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial |
| title_sort | mat2a inhibitor ag 270 s095033 in patients with advanced malignancies a phase i trial |
| url | https://doi.org/10.1038/s41467-024-55316-5 |
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