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

PI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTORC1-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates 4EBP1 and S6K, and exhibits selectivity for mTORC1 over mTORC2. Here, 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 IV 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- to 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 ongoing for >6 months as of the June 2024 data cut. Clearance of PI3K/mTOR pathway variants among circulating tumor DNA 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.