The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial

作者：Alison M. Schram, Abdul Rafeh Naqash, Eric B. Haura, Jonathan W. Riess, Susanna V. Ulahannan, Sai‐Hong Ignatius Ou, Pamela N. Münster, Michael L. Cheng, W. Clay Gustafson, Bojena Bitman, Robert J. Friedman, R. D. Penn, Sumit Kar, Vidya Seshadri, Zhican Wang, Tao Lin, Yu Chi Yang, Mallika Singh, Howard A. Burris, Justin Meyerowitz · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-2112 · 被引用次数：7 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Viral-associated cancers and disorders、Oral health in cancer treatment

PURPOSE: PI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTOR complex 1 (mTORC1)-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates eukaryotic initiation factor 4E-binding protein-1 and S6 kinase and exhibits selectivity for mTORC1 over mTORC2. In this study, we report results from a first-in-human, dose-escalation study of RMC-5552 in patients with advanced solid tumors (NCT04774952). PATIENTS AND METHODS: The safety, tolerability, pharmacokinetics, and preliminary activity of RMC-5552 (1.6-16 mg intravenous infusion weekly) were evaluated in 57 patients. RESULTS: The most common treatment-related adverse events were mucositis (49%), nausea (44%), and fatigue (42%). Consistent with mTORC1 selectivity, treatment-related hyperglycemia incidence was generally low (4%) and not dose limiting. Additionally, we tested potential prophylaxis with tacrolimus mouthwash (TM), which was predicted to block the mechanism of action of RMC-5552 locally and alleviate treatment-related oral mucositis. Between 8- and 12-mg dosing, mucositis was 65% without TM versus 31% with TM. In this study, the disease control rate was 64%, and one patient with PTEN- and PIK3CA-altered endometrial cancer had a complete response and treatment was ongoing for >6 months as of the June 2024 data cut. Clearance of PI3K/mTOR pathway variants among ctDNA was observed. CONCLUSIONS: The success of TM-mediated prophylaxis and th...