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

Author

Listed:
  • 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
    University College of London)

  • 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.
    Servier)

  • Rohini Narayanaswamy

    (Servier)

  • Amel Sadou-Dubourgnoux

    (Servier)

  • Michael Cooper

    (Agios Pharmaceuticals Inc.
    Servier)

  • Vasileios Askoxylakis

    (Servier)

  • Howard A. Burris

    (Sarah Cannon Research Institute)

  • Josep Tabernero

    (Vall d’Hebron Institute of Oncology)

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.

Suggested Citation

  • 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-Frai, 2025. "MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55316-5
    DOI: 10.1038/s41467-024-55316-5
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