1. Fuerst, Mark L.

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BOSTON-An investigational inhibitor of an enzyme that occurs in about 15 percent of human cancers shows signs of activity in select patients with solid tumors, according to a new study. The therapeutic AG-270 is a first-in-class, oral, potent, reversible inhibitor that targets the protein MAT2A. It was found to be safe and tolerable in patients who had solid tumors in which both copies of the MTAP gene were deleted. This gene encodes the metabolic enzyme methylthioadenosine phosphorylase.

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"About 15 percent of all human cancers have both copies of the MTAP gene deleted," said Rebecca S. Heist, MD, a medical oncologist at Massachusetts General Hospital Cancer Center. "Research into the biology of these cancers led to the discovery that cancer cells with MTAP deletion are selectively vulnerable to inhibition of the MAT2A enzyme.


"MAT2A inhibition leads to the molecule S-adenosylmethionine (SAM) being produced at lower levels than normal," said Heist, who is also Associate Professor of Medicine at Harvard Medical School. "The reduction in SAM levels is sufficient to slow the growth of cancer cells with MTAP deletion, but does not affect healthy cells in which the MTAP gene is intact."


Heist presented the results of a phase I clinical trial at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. The preliminary results are from the ongoing first-in-human phase I clinical trial of AG-270. The main goal of the trial was to determine the maximum tolerated dose of the investigational therapeutic.


Study Details

So far, Heist and colleagues have enrolled 39 patients who had an advanced solid tumor with MTAP deletion, or CDKN2A loss, which usually correlates with MTAP deletion. The most common cancers were bile duct cancer (seven patients), pancreatic cancer (seven patients), mesothelioma (four patients), and non-small cell lung cancer (four patients). The doses of AG-270 tested in the trial ranged from 50 mg once daily to 400 mg once daily and 200 mg twice daily.


One patient who had a high-grade neuroendocrine tumor of the lung had a partial response after treatment with 200 mg AG-270 once daily. Eight other patients, treated with doses ranging from 100 mg to 400 mg once daily, had stable disease. As of mid-August 2019, the partial response was ongoing 4.4 months after the patient started treatment. Stable disease was ongoing for two patients, including one patient who had a sex cord-stromal tumor, who had received treatment for more than 1 year.


"Importantly, the reduction in plasma SAM levels was similar across the entire range of doses we evaluated," noted Heist. "The 60-70 percent reduction achieved was in the same range that was associated with maximal inhibition of tumor growth in preclinical models."


The therapeutic was well-tolerated. Asymptomatic, exposure-dependent increases in unconjugated bilirubin were observed starting at 100 mg once daily, consistent with the known potential of AG-270 to inhibit the UGT1A1 gene. Three patients at 100 mg once daily, 150 mg once daily, and 200 mg twice daily doses developed grade 2 and 3 diffuse erythematous rashes during the second week of dosing that resolved within 1 week of stopping treatment. Exposure-dependent, reversible decreases in platelet counts were first observed at 200 mg once daily and were grade 3 and 4 in severity at 200 mg twice daily. Two patients treated at 200 mg twice daily developed reversible but dose-limiting grade 3 and 4 increases in liver enzymes. The maximum tolerated dose of AG-270 was determined to be 200 mg once daily.


"We are pleased that the study accomplished its main objective, which was to identify a safe AG-270 dose and schedule that would lower plasma SAM levels to the extent required for antitumor activity," stated Heist. "Although AG-270 demonstrated some evidence of single-agent activity, based on preclinical data, we believe that it will have its greatest benefit when combined with taxane-based chemotherapy. There are plans to test AG-270 in combination with taxanes in the clinic in the near future."


The main limitation of the study, she said, is that the trial enrolled patients with a wide range of advanced solid tumors, most of which are inherently resistant to standard treatments and had progressed despite standard treatments. This makes evaluating the single-agent activity of AG-270 in cancer treatment difficult in this study, Heist noted.


Mark L. Fuerst is a contributing writer.


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