MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: A phase I trial Journal Article
| Authors: | Gounder, M.; Johnson, M.; Heist, R. S.; Shapiro, G. I.; Postel-Vinay, S.; Wilson, F. H.; Garralda, E.; Wulf, G.; Almon, C.; Nabhan, S.; Aguado-Fraile, E.; He, P.; Romagnoli, M.; Hossain, M.; Narayanaswamy, R.; Sadou-Dubourgnoux, A.; Cooper, M.; Askoxylakis, V.; Burris, H. A.; Tabernero, J. |
| Article Title: | 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 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. © The Author(s) 2025. |
| Keywords: | immunohistochemistry; adult; cancer chemotherapy; clinical article; controlled study; human tissue; aged; middle aged; primary tumor; unclassified drug; gene deletion; genetics; clinical trial; drug tolerability; fatigue; advanced cancer; area under the curve; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; drug withdrawal; monotherapy; side effect; solid tumor; systemic therapy; antineoplastic agents; gemcitabine; paclitaxel; cancer patient; pancreas cancer; antineoplastic agent; neoplasm; neoplasms; metabolism; controlled clinical trial; liver toxicity; multiple cycle treatment; anemia; bleeding; nausea; thrombocytopenia; vomiting; protein; cancer pain; tumor biopsy; pathology; enzyme inhibitor; enzyme activity; inhibitor; docetaxel; abdominal pain; drug hypersensitivity; dyspnea; pneumonia; bilirubin; drug fatality; maculopapular rash; fluorescence in situ hybridization; enzyme inhibitors; multicenter study; pancreatitis; malignant mesothelioma; single drug dose; gene loss; sepsis; retina hemorrhage; safety; hyperbilirubinemia; time to maximum plasma concentration; drug blood level; liver function test; maximum tolerated dose; phase 1 clinical trial; cyclin dependent kinase inhibitor 2a; drug half life; tumor; drug therapy; drug dose increase; liver biopsy; atrial fibrillation; bilirubin blood level; disease exacerbation; plasma; supraventricular tachycardia; tachycardia; liver injury; plasma concentration-time curve; blurred vision; bile duct cancer; ecg abnormality; sinus tachycardia; concentration (composition); non small cell lung cancer; s-adenosylmethionine; decreased appetite; autoimmune hepatitis; maximum permissible dose; disease prevalence; t wave; multiple drug dose; optic nerve disease; methionine adenosyltransferase; response evaluation criteria in solid tumors; high throughput sequencing; 5' methylthioadenosine phosphorylase; humans; human; male; female; article; patient history of chemotherapy; ecog performance status; auc (0-24 h); maximum concentration; transferase inhibitor; ademetionine; first in human study; trough concentration; drug induced hepatitis; ag 270 s095033; ag 270s 095033; methionine adenosyltransferase 2a; mat2a protein, human; auc (0 tau); immune allergic hepatitis; optic disc hemorrhage; proof of mechanism; reversible liver injury |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-06 |
| Start Page: | 423 |
| Language: | English |
| DOI: | 10.1038/s41467-024-55316-5 |
| PUBMED: | 39762248 |
| PROVIDER: | scopus |
| PMCID: | PMC11704051 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
