Abstract C020: First-in-human phase 1/1b trial of the first-in-class bi-steric mTORC1-selective inhibitor RMC-5552 in patients with advanced solid tumors
Authors: Schram Alison M , Naqash Abdul Rafeh , Haura Eric B , Riess Jonathan W , Ulahannan Susanna V , Ou Sai-Hong I , Capasso Anna , Munster Pamela N , Cheng Michael L , Gustafson W Clay , Bitman Bojena , Kar Sumit , Wang Zhican , Tao Lin , Meyerowitz Justin G , Burris Howard A 
Published: December 2023

Abstract
Activation of the mTOR pathway plays a role in the oncogenesis and progression of many cancer types, and is frequently co-altered in RAS-driven tumors. First-generation mTORC1-selective inhibitors were limited by incomplete inhibition of 4EBP1 phosphorylation, while second-generation pan-mTOR inhibitors had a low therapeutic index due to mTORC2-mediated toxicity such as hyperglycemia. RMC-5552 is a first-in-class third-generation bi-steric mTOR inhibitor that is mTORC1-selective via its FKBP12-binding moiety and potently inhibits phosphorylation of the 4EBP1 tumor suppressor via a linked ATP-competitive moiety, addressing these key limitations of prior mTOR inhibitors in preclinical models. RMC-5552 is being investigated in a Phase I/Ib study (NCT04774952). Eligible patients (pts) were ≥18 yrs old with ECOG 0-1 and had advanced solid tumors that had failed or were ineligible for standard-of-care treatments. Pts received RMC-5552 as a weekly infusion. To address mucositis, a common toxicity in pts treated with mTOR inhibitors, pts prophylactically used dexamethasone mouthwash either alone or with tacrolimus mouthwash (TM), which binds to the RMC-5552 presenter protein FKBP12. Objectives included assessment of safety/tolerability (CTCAEv5), defining the maximum tolerated and recommended Phase 2 doses, pharmacokinetics, and preliminary efficacy (RECIST v1.1). As of June 12, 2023, 47 pts have been evaluated at 6 dose levels from 1.6 mg to 12 mg. The most common (&gt; 20%) treatment-related adverse events (TRAE, any grade) were stomatitis/mucositis (45%), fatigue (40%), nausea (38%), decreased appetite (32%), and vomiting (23%). Treatment-related events of hyperglycemia occurred in 4% of pts (both grade 2) and were not dose limiting. The most common grade 3 TRAE at dose levels ≥6 mg was mucositis/stomatitis, which was dose-dependent and limited tolerability in the absence of TM. Between 8 and 12 mg, the rate of treatment related stomatitis/mucositis was 65% (15% grade 3) in pts treated without TM (N = 20) versus 30% (no grade 3) in pts treated with TM (N = 10). TM prophylaxis enabled dose escalation beyond dose levels previously considered intolerable due to mucositis (10-12 mg; escalation ongoing), and unbound plasma exposures at 8-12 mg were within the range that induced significant anti-tumor activity in preclinical models. The disease control rate was 67% among efficacy evaluable pts (N = 39). One pt with a salivary gland tumor harboring a PTEN mutation had a confirmed partial response (PR) with 78% reduction and 16 months duration of response. In addition, molecular responses of circulating tumor DNA were observed in pts with mTOR pathway variants. Updated efficacy results will be presented. These early data indicate that RMC-5552 monotherapy is tolerated at doses predicted to be efficacious, and that selective inhibition of mTORC1 alleviates mTORC2-mediated toxicity. Dose escalation is ongoing, and mucositis prophylaxis has enabled further dose intensification for future combination studies with RAS(ON) inhibitors.
Citation Format: Alison M Schram, Abdul Rafeh Naqash, Eric B Haura, Jonathan W Riess, Susanna V Ulahannan, Sai-Hong I Ou, Anna Capasso, Pamela N Munster, Michael L Cheng, W Clay Gustafson, Bojena Bitman, Sumit Kar, Zhican Wang, Lin Tao, Justin G Meyerowitz, Howard A Burris. First-in-human phase 1/1b trial of the first-in-class bi-steric mTORC1-selective inhibitor RMC-5552 in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C020.