Phase Ib and dose-expansion study of GSK3326595, a PRMT5 inhibitor as monotherapy and in combination with pembrolizumab in patients with advanced cancers.
M M Gounder, P Martin-Romano, A Italiano, L L Siu, P A Cassier, G S Falchook, I S Lossos, D W Rasco, J F Hilton, M A McKean, F L Opdam, J Strauss, M De Jonge, J S P Vermaat, T Crossman, M Zajac, A Tarkar, F Gonzalez Carreras, B E Kremer, O Barbash, S Segal, R Parasrampuria, S Postel-Vinay
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引用次数: 0
Abstract
Background: Protein arginine methyltransferase 5 inhibition often leads to a decrease in cell growth and survival in cancer cell lines. GSK3326595 is a first-generation protein arginine methyltransferase 5 inhibitor.
Patients and methods: METEOR-1 was a first-in-human, open-label, multicenter, three-part phase I study (NCT02783300) in patients with solid tumors and non-Hodgkin lymphoma (NHL). The objectives of part 1 were to determine the recommended phase II dose (RP2D), assess safety, evaluate preliminary clinical activity, and study the pharmacokinetics of oral GSK3326595 monotherapy. Part 2 enrolled patients at the RP2D to further evaluate clinical activity and safety. Part 3 explored the RP2D of GSK3326595 with pembrolizumab.
Results: A total of 288 patients were treated. In part 1, 69 patients received once daily (od) or twice a day (b.i.d.) GSK3326595 in doses ranging from 12.5 to 600 mg/day. In part 2, 218 patients received either 400 mg or 300 mg od, with the RP2D amended from 400 mg to 300 mg od due to toxicities. In part 3, 10 patients received GSK3326595 at 100 mg/day with pembrolizumab 200 mg intravenously every 3 weeks. Pharmacokinetics revealed that GSK3326595 was rapidly absorbed (Tmax: 2-3 hours), with a mean terminal half-life of 4-6 hours. Dose-dependent increases in plasma exposure (Cmax and AUC) were observed with both od and b.i.d. dosing. The most common adverse events at the RP2D included fatigue (57%), nausea (48%), and anemia (48%). Four partial responses (PRs) were observed in part 1 at doses of 200 mg (n = 2), 300 mg (n = 1), and 400 mg (n = 1). Two complete responses and one PR were seen in NHL [i.e. follicular (n = 2) lymphoma, diffuse large B-cell lymphoma (n = 1)], one PR in adenoid cystic carcinoma, and one PR in HR-positive breast cancer in part 2. No responses were observed in part 3.
Conclusions: GSK3326595 monotherapy demonstrated modest antitumor activity. Further research in adenoid cystic carcinoma and NHL is warranted.
期刊介绍：
Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine.
The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings.
Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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