RMC-5552

These findings are consistent with a phase I trial of bi-steric mTORC1 inhibitor RMC-5552, showing anti-tumor activity in patients with EC. PDXs with KRAS co-mutations regrew after RMC-6272 treatment, which was prevented by the addition of the RAS(ON) multi-selective inhibitor RMC-7977...Single mutant tumors are sensitive to PI3K inhibition but those with both mutations are insensitive to PI3K or AKT inhibition but are exquisitely dependent on mTORC1 kinase. This provides strong preclinical rationale for targeting mTORC1, alone or combined with RAS inhibition (in RAS co-mutant tumors), as an effective therapeutic strategy.

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.

P1, N=48, Recruiting, Nicholas Butowski | Suspended --> Recruiting

This demonstrates that mTORC1-driven 4E-BP1/eIF4E rapamycin-insensitive translational control overrides transcriptional control of ECM genes. Inhibition by RMC-5552 of ECM and fibroblast activation may result in destruction of CSC-like LAM cells and provide more enduring therapy for LAM patients.

P1, N=48, Suspended, Nicholas Butowski | Trial completion date: Dec 2025 --> Apr 2030 | Trial primary completion date: Dec 2025 --> Apr 2030

RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic MYC amplifications and reduces MYC protein levels in vivo. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.

We demonstrate that combining the CDK4/6 inhibitor palbociclib with the mTORC1-selective inhibitor RMC-5552 synergistically inhibits the growth of tRCC cells in vitro and of tRCC xenografts in vivo , where the combination is well-tolerated. This proof-of-concept study provides preclinical evidence supporting CDK4/6 inhibitor-based combination regimens tailored to tRCC biology, offering a foundation for future clinical studies in tRCC, which currently has no clear standard of care.

P1, N=48, Suspended, Nicholas Butowski | Recruiting --> Suspended

P1, N=58, Completed, Revolution Medicines, Inc. | Active, not recruiting --> Completed | N=108 --> 58

Rapamycin inhibition of LAF growth was rapidly reversed, but RMC-5552 inhibition was more durable. RMC-5552, through its potential to eradicate LAM cancer SLS cells, may have therapeutic benefit in LAM and other diseases with mTORC1 hyperactivity.

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.