“About 15 percent of all human cancers have both copies of the MTAP gene deleted,” said Rebecca S. Heist, MD
, medical oncologist at Massachusetts General Hospital Cancer Center in Boston. “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,” explained 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.”
AG-270 inhibits MAT2A. Heist is presenting preliminary results 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.
As of mid-August 2019, Heist and colleagues had enrolled in the trial 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 a day to 400 mg once a day and 200 mg twice a day.
Reversible decreases in platelet counts were seen in patients who received 200 mg AG-270 once a day. Two of the six patients treated with 200 mg AG-270 twice a day had grade 3 or 4 decreases in their platelet counts and two had grade 3 or 4 increases in liver enzymes. Three patients, treated with 100, 150, and 200 mg twice daily, had grade 2 or 3 rashes. The maximum tolerated dose of AG-270 was determined to be 200 mg once a day.
“Importantly, the reduction in plasma SAM levels was similar across the entire range of doses we evaluated,” said Heist. “The 60 to 70 percent reduction achieved was in the same range that was associated with maximal inhibition of tumor growth in preclinical models.”
One patient who had a high-grade neuroendocrine tumor of the lung had a partial response after treatment with 200 mg AG-270 once a day. Eight other patients, treated with doses ranging from 100 mg to 400 mg once a day, 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 chord stromal tumor, who had received treatment for more than one year.
“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,” said 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.”
According to Heist, the main limitation of the study 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, she noted.
This study was sponsored by Agios Pharmaceuticals. Heist has received consulting honoraria from Boehringer Ingelheim, Novartis, Apollomics, and Tarveda Therapeutics. In addition, she has received research funding for clinical trials to her institution from Genentech/Roche, Novartis, Celgene, Millennium Pharmaceuticals, Debiopharm, Exelixis, Agios, Mirati, AbbVie, Peregrine, and Daiichi Sankyo.
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