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.

Fig. 1

Phase 1 study schematic (ClinicalTrials.gov NCT03435250; EudraCT 2017-004384-13).

Fig. 2. Waterfall plot of change in tumor size; CT and PET images for two patients achieving partial responses; Swimmer’s plot of treatment duration and response.

a Waterfall plot of best percentage change in tumor size by RECIST. b Serial axial CT/PET images of a 54-year-old male patient with high-grade neuroendocrine carcinoma of the lung treated with single agent AG270/S095033 at a dose of 200 mg QD. White arrows indicate location of tumor. PR partial response. c Serial axial CT images of a 53-year-old male patient with a refractory sex cord stromal cell cancer treated with single agent AG270/S095033 at a dose of 100 mg QD. White arrows indicate location of tumor. PR partial response. d Swimmer’s plot of treatment duration and best response by RECIST. BDC bile duct cancer, MM malignant mesothelioma, NSCLC non-small cell lung cancer, PC pancreatic cancer.

Fig. 3. AG-270/S095033 pharmacokinetics.

a AG-270/S095033 concentration-time profile after multiple-dose administration at steady state (C1D15). Geometric mean ± SD is shown. b AG-270/S095033 AUC0-24h at steady state (C1D15). Box denotes 25th to 75th percentiles, horizontal bar the mean, and dotted bar the median, with whiskers extending to the minimum and maximum values. (a, b) AUC0-24 h AUC from 0 to 24 h, ss steady state. AUC0-24, ss = area under the concentration × time curve at steady state from time 0 to 24 h, BID twice daily, QD once daily, SD standard deviation, hr hour, n number of patients evaluated in each cohort, ng/mL nanogram per milliliter.

Fig. 4. Clinical pharmacodynamic activity of AG-270/S095033.

a Reductions in plasma SAM concentration at steady state (C1D15) in patients. Average reductions in plasma SAM concentration are within the range associated with maximum tumor growth inhibition in preclinical models (60–80%). b Increase in plasma methionine concentration at steady state (C1D15) in patients. In (a, b), box denotes 25th to 75th percentiles, horizontal bar the mean, and dotted bar the median, with whiskers extending to the minimum and maximum values. n indicates the number of patients evaluated in each cohort for each biomarker (SAM or methionine). c, d SDMA assessment by IHC in paired tumor biopsies collected before treatment and upon treatment of patients at C1D28. In c, H-scores found in 9 patients treated with AG-270/S095033 at the indicated doses, are shown (p-value = 0.055, two sided Wilcoxon matched-pairs test). In d, an example of SDMA staining is shown for a NSCLC patient with 39% SDMA reduction after 1 cycle of treatment with AG-270/S095033 at 50 mg QD.

Fig. 5. Mechanism of action of AG-270/S095033.

The MAT2A inhibitor AG-270/S095033 leads to a reduction in SAM concentrations and inhibition of PRMT5 activity in MTAP-deleted tumors. This results in a decrease in SDMA residues on target proteins involved in mRNA splicing and the induction of cell death.