Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy
- Study type
- Other
- Study name
- RMC-7977
- Design
- Preclinical study (preclinical models of RAS-dependent cancer); this paper is not a clinical trial
- Sample size
- Preclinical study; no patients (details of the models in the full text of the paper)
- Source
- Nature · 2024
In plain words
Genes of the RAS family are among the genes most often mutated in cancer, but approved drugs exist only for one specific type of mutation (KRAS G12C). This laboratory and animal study looked at a new drug called RMC-7977 that can block many different forms of the RAS protein in their active state. In preclinical models the drug shrank tumours and was well tolerated. These results have not yet been tested in patients, and a related drug (RMC-6236) is being studied in clinical trials.
Key results
Treatment arms and regimens
RMC-7977, a reversible tri-complex RAS inhibitor that targets the active form (RAS(ON)) of mutant and wild-type KRAS, NRAS and HRAS (a multi-selective RAS(ON) inhibitor). Dose details in the full text of the paper.
Source of the regimen details: Abstract of the paper; dose details in the full text of the paper
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
No patients were enrolled in this study. Activity of the drug was studied in preclinical models of RAS-addicted cancer with various RAS genotypes, especially models with mutations at codon 12 of KRAS (KRAS G12X), and in KRAS G12C models resistant to KRAS(G12C) inhibitors. Details of the models are given in the full text of the paper.
Endpoints
This is a preclinical study. Based on the abstract, what was assessed included antitumour activity against RAS-addicted tumours of various genotypes, tumour regression, tolerability in preclinical models, and growth inhibition of KRAS G12C models resistant to KRAS(G12C) inhibitors. No formal primary or secondary endpoint is defined in the abstract.
Safety and side effects
Based on the abstract, RMC-7977 was "well tolerated" in diverse preclinical models of RAS-addicted cancer. No data on grade 3 or higher adverse events in humans are reported, because this is a preclinical study.
Clinical significance and place in guidelines
This paper is a preclinical study and on its own has no effect on patient care, and RMC-7977 is not a drug approved for clinical use. The abstract only shows that multi-selective RAS(ON) inhibition could be a strategy for treating RAS-addicted cancers, including those with KRAS mutations other than G12C and with resistance to KRAS(G12C) inhibitors. A related inhibitor, RMC-6236, is under clinical evaluation in patients with KRAS-mutant solid tumours (NCT05379985). The status of drug approval and clinical guideline recommendations should be checked separately.
Limitations
This is a preclinical study, and its results were obtained in cell and animal models; efficacy and safety in humans are not established by these data. The abstract gives no quantitative data (such as percentage of tumour regression or dose), and the details are in the full text of the paper. Several authors are affiliated with the drug's manufacturer (Revolution Medicines).
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.