MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial

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 and Josep Tabernero ()
Additional contact information
Mrinal Gounder: Memorial Sloan Kettering Cancer Center; Weill Cornell Medical College
Melissa Johnson: Sarah Cannon Research Institute
Rebecca S. Heist: Massachusetts General Hospital
Geoffrey I. Shapiro: Dana-Farber Cancer Center
Sophie Postel-Vinay: Institut Gustave Roussy and U981 INSERM
Frederick H. Wilson: Yale Cancer Center
Elena Garralda: Vall d’Hebron Institute of Oncology
Gerburg Wulf: Beth Israel Deaconess Medical Center
Caroline Almon: Agios Pharmaceuticals Inc.
Salah Nabhan: Agios Pharmaceuticals Inc.
Elia Aguado-Fraile: Agios Pharmaceuticals Inc.
Peng He: Servier
Mathilde Romagnoli: Servier
Mohammad Hossain: Agios Pharmaceuticals Inc.
Rohini Narayanaswamy: Servier
Amel Sadou-Dubourgnoux: Servier
Michael Cooper: Agios Pharmaceuticals Inc.
Vasileios Askoxylakis: Servier
Howard A. Burris: Sarah Cannon Research Institute
Josep Tabernero: Vall d’Hebron Institute of Oncology

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55316-5

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