First-in-human trial of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting -- direct clinical confirmation that sparing mTORC2 avoids the metabolic toxicity seen with rapalogs/active-site inhibitors, while still achieving a 64% disease control rate.
| Evidence tier | B Direct human evidence |
| Study type | 2 - Human Clinical Trial |
| Model system | Human (Phase 1 dose escalation, n=57, advanced solid tumors, NCT04774952) |
| Journal | Clinical Cancer Research |
| Year | 2025 |
| Peer reviewed | Yes |
| Source | DOI 10.1158/1078-0432.CCR-25-2112 · PMID 41056387 · Free full text (PMC12666311) |
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). The safety, tolerability, pharmacokinetics, and preliminary activity of RMC-5552 (1.6-16 mg intravenous infusion weekly) were evaluated in 57 patients. 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. The success of TM-mediated prophylaxis and the clearance of selected variants in ctDNA are concordant with selective, on-mechanism, antitumor activity following RMC-5552 treatment. These data show that RMC-5552, the first bi-steric mTORC1-selective inhibitor in the clinic, is active at tolerable doses and that selective inhibition of mTORC1 alleviates mTORC2-mediated hyperglycemia, overcoming a key limitation of prior mTOR inhibitors.
| Intervention | RMC-5552 (bi-steric mTORC1-selective inhibitor), 1.6-16mg IV weekly |
| Target | mTORC1 (4E-BP1, S6K1), sparing mTORC2 |
| Model | Human |
| Effect | 64% disease control rate; low (4%) treatment-related hyperglycemia confirming mTORC2 sparing |