RMC-5552

P1, N=48, Recruiting, Nicholas Butowski | Active, not recruiting --> Recruiting

Employing human NF2-deficient meningioma lines, we compared mTOR inhibitors rapamycin (first-generation), INK128 (second-generation), and RMC-6272 (third-generation) using in vitro dose-response testing, cell-cycle analysis, and immunoblotting. Furthermore, in vivo studies in mice revealed effective blockage of meningioma growth by RMC-6272, compared with vehicle controls. Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.

P1, N=108, Active, not recruiting, Revolution Medicines, Inc. | Recruiting --> Active, not recruiting

P1, N=48, Active, not recruiting, Nicholas Butowski | Recruiting --> Active, not recruiting

P1, N=48, Recruiting, Nicholas Butowski | Not yet recruiting --> Recruiting

In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS shows increased antitumor activity in a preclinical model of KRAS mutant NSCLC that exhibits resistance to KRAS inhibitor monotherapy.

P1, N=48, Not yet recruiting, Nicholas Butowski | Initiation date: Nov 2022 --> Feb 2023

P1, N=48, Not yet recruiting, Nicholas Butowski

Our study demonstrates that RMC-6272, a novel bi-steric mTORC1 inhibitor, had a potent multifactorial effect on diminishing HB and HCC growth in relevant murine models. These observations further solidify the potential use of mTORC1 inhibitors as therapeutic agents for CTNNB1-mutated HCCs and in most HB cases. The bi-steric mTORC1 inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952).

First-line HCC therapy atezolizumab with bevacizumab increased patient 6-month PFS from 37% to 55% relative to sorafenib, a multi-kinase inhibitor currently serving as a standard-of-care treatment. Although immunotherapies provide survival benefits, reported patient response and disease control rates were 27% and 74%, respectively, highlighting the need for novel therapeutic agents that can re-establish responsiveness to immunotherapies and enhance their therapeutic effects.Revolution Medicines has developed a class of selective mTORC1 inhibitors, termed ‘bi-steric’, which comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor...The bi-steric mTORC1 inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952). These preclinical data highlight a prospective anti-cancer therapeutic opportunity for mTORC1 selective inhibitors in combination with immune checkpoint inhibitors in MYC-driven cancers.

The results suggest that dysregulation of TORC1 activity is an important driver of endometrial carcinomas with coexistent PTEN inactivation and PI3K mutations and that selective TORC1 kinase inhibitors may prove to be useful therapeutics in this context. The bi-steric mTORC1 kinase inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952).

RMC-5552 is the first clinical candidate of this class and clinical testing is planned in 2021...Rapamycin, MLN0128 and both RM compounds markedly reduced kidney tumor burden in Tsc2+/- A/J mice after four weeks of treatment...This is the first time that clear evidence for cell death after mTORC1 inhibition has been seen in TSC rodent models. In summary, RM-001 and RM-006 demonstrate improved in vitro and in vivo inhibition of mTORC1 in comparison to rapamycin, and induced more cell death in TSC2 null tumors in vivo, indicating the potential of bi-steric mTORC1-selective inhibitors as a novel therapeutic strategy to treat tumors with mTORC1 dysregulation.

These treatments include first-line therapy Sorafenib and second-line combination therapy nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4)...Revolution Medicines has developed a class of selective mTORC1 inhibitors, termed ‘bi-steric’, which comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor...These preclinical data highlight a potential therapeutic opportunity for the investigational bi-steric mTORC1 inhibitor RMC-5552 in combination with immune checkpoint inhibitors to overcome MYC-mediated immune suppression. Under this potential therapeutic paradigm HCC patient survival may be extended via a dual mechanism that reduces MYC levels via 4EBP1 reactivation and that rescues anti-tumor immune surveillance.