Elironrasib Receives FDA Breakthrough Therapy Designation for Pretreated KRAS G12C+ NSCLC

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The FDA has granted breakthrough therapy designation to elironrasib (RMC-6291) for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring KRAS G12C mutations who have been previously treated with chemotherapy and immunotherapy and are naive to a KRAS G12C inhibitor.1

The designation for elironrasib—a RAS ON, G12C-selective inhibitor—was based on data from the phase 1 RMC-6921-001 trial (NCT05462717), which is evaluating the agent as monotherapy in patients with KRAS G12C–mutated advanced solid tumors.

“There continues to be a need for new targeted therapies for patients with RAS-addicted cancers, and this breakthrough therapy designation from the FDA highlights the therapeutic potential of elironrasib, a differentiated inhibitor, for patients with KRAS G12C[–mutated] lung cancer,” Mark A. Goldsmith MD, PhD, chief executive officer and chairman of Revolution Medicines, stated in a news release. “Coming shortly after daraxonrasib (RMC-6236) was granted a designation for patients with advanced RAS-mutant pancreatic cancer, this designation for elironrasib further validates our innovative product engine as a source for novel potential treatment approaches for patients with RAS-mutant cancers.”

Data from RMC-6921-001 presented at the 2023 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics demonstrated that in patients with NSCLC who were naive to a KRAS G12C OFF inhibitor (n = 7) achieved an overall response rate (ORR) of 43%, with all responses being partial.2 The remaining 57% of patients experienced stable disease, translating to a disease control rate (DCR) of 100%. In patients who were previously exposed to a KRAS G12C OFF inhibitor (n = 10), the ORR was 50%, comprised exclusively of partial responses, and the DCR was 100%. In the overall NSCLC population, the median time to response was 1.3 months (range, 1.1-4.1), and the median time on treatment was 3.5 months (range, 0.3-9.8).

Findings also showed that patients with KRAS G12C–mutant colorectal cancer (CRC) who were naive to a KRAS G12C OFF inhibitor (n = 20) experienced an ORR of 40% and a DCR of 80%. The median time to response and median time on treatment were 1.4 months (range, 1.2-4.1) and 2.4 months (range, 0.3-7.9), respectively.

Regarding safety in all patients (n = 63), no grade 4 or 5 adverse effects (AEs) or serious AEs were reported. Treatment-related AEs (TRAEs) led to dose reductions in 14% of patients and treatment discontinuation in 2% of patients. The most common any-grade TRAEs reported in at least 10% of patients included diarrhea (29%), nausea (27%), prolonged ECG QT interval (25%), fatigue (13%), vomiting (13%), and increased aspartate aminotransferase levels (11%).

Elironrasib Background and RMC-6921-001 Design

Elironrasib is a potent, covalent, KRAS G12C ON inhibitor comprised of a novel tricomplex mechanism intended to selectively target the GTP-bound KRAS G12C protein.

The phase 1 study enrolled patients at least 18 years of age with advanced solid tumors harboring KRAS G12C mutations who received prior standard therapy; notably, prior treatment with KRAS G12C OFF inhibitors was allowed. Patients were also required to have an ECOG performance status of 0 or 1, and patients with previously treated/stable brain metastases were permitted to enroll.

In dose escalation, oral elironrasib was given at doses of 50 mg once per day, 100 mg once per day, 200 mg once per day, 100 mg twice per day, 200 mg twice per day, 300 mg twice per day, and 400 mg twice per day.

The primary end points of the trial were safety/tolerability, pharmacokinetics, and antitumor activity.

References

1. Revolution Medicines announces FDA breakthrough therapy designation for elironrasib. News release. Revolution Medicines. July 23, 2025. Accessed July 24, 2025. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy-0
2. Jänne PA, Bigot F, Papadopoulos K, et al. Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment. Mol Cancer Ther. 2023;22(suppl 12):PR014. doi:10.1158/1535-7163.TARG-23-PR014