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

Alison M Schram1, Abdul Rafeh Naqash2,3, Eric B Haura4

  • 1Memorial Sloan Kettering Cancer Center, New York, New York.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 7, 2025
PubMed
Abstract

Insights

RMC-5552, a novel mTORC1 inhibitor, shows promising activity and tolerability in advanced solid tumors. Tacrolimus mouthwash effectively reduced mucositis, demonstrating selective, on-mechanism antitumor effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The PI3K/mTOR pathway is crucial in cancer development and progression.
  • RMC-5552 is a novel bi-steric inhibitor targeting mTOR complex 1 (mTORC1) selectively over mTOR complex 2 (mTORC2).

Purpose of the Study:

  • To evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of RMC-5552 in a first-in-human dose-escalation study.
  • To assess the efficacy of tacrolimus mouthwash (TM) in preventing RMC-5552-induced oral mucositis.

Main Methods:

  • A dose-escalation study of RMC-5552 (1.6-16 mg IV weekly) was conducted in 57 patients with advanced solid tumors.
  • Safety, tolerability, pharmacokinetics, and preliminary activity were assessed.
  • Tacrolimus mouthwash was tested for mucositis prophylaxis.

Main Results:

  • The most frequent adverse events included mucositis (49%), nausea (44%), and fatigue (42%).
  • Hyperglycemia incidence was low (4%), consistent with mTORC1 selectivity.
  • Tacrolimus mouthwash reduced mucositis rates from 65% to 31% between 8- and 12-mg doses.
  • Disease control rate was 64%, with one complete response in endometrial cancer.
  • Clearance of PI3K/mTOR pathway variants in circulating tumor DNA (ctDNA) was observed.

Conclusions:

  • RMC-5552 is the first bi-steric mTORC1-selective inhibitor clinically tested, showing activity at tolerable doses.
  • Selective mTORC1 inhibition with RMC-5552 overcomes hyperglycemia limitations of earlier mTOR inhibitors.
  • Tacrolimus mouthwash prophylaxis and ctDNA variant clearance support RMC-5552's selective, on-mechanism antitumor activity.

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