Abstract
Protein arginine methyltransferase 5 (PRMT5) inhibition often leads to a decrease in cell growth and survival in cancer cell lines. GSK3326595 is a first-generation PRMT5 inhibitor.
METEOR-1 was a first-in-human, open-label, multicenter, three-part phase 1 study (NCT02783300) in patients with solid tumors and non-Hodgkin lymphoma (NHL). Objectives of part 1 were to determine the recommended phase 2 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.
A total of 288 patients were treated. In part 1, 69 patients received QD or BID GSK3326595 in doses ranging from 12.5-600 mg/day. In part 2, 218 patients received either 400 mg or 300 mg QD, with the RP2D amended from 400 mg to 300 mg QD 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 (T
: 2-3 hours), with a mean terminal half-life of 4-6 hours. Dose-dependent increases in plasma exposure (C
and AUC) were observed with both QD and BID dosing. The most common adverse events (AEs) 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 1 PR were seen in NHL (ie, follicular [n=2] lymphoma, diffuse large B-cell lymphoma [n=1]), 1 PR in adenoid cystic carcinoma, and 1 PR in HR+ breast cancer in part 2. No responses were observed in part 3.
GSK3326595 monotherapy demonstrated modest antitumor activity. Further research in ACC and NHL is warranted.