Elironrasib Earns FDA Breakthrough Designation for KRAS G12C-Mutant NSCLC

The agent exhibited competitive antitumor activity, which included compelling objective response rate and progression-free survival data, as well as differentiated safety and tolerability outcomes.

The FDA has granted breakthrough therapy designation to elironrasib (RMC-6291) as a monotherapy for adult patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC) who have received prior chemotherapy and immunotherapy but who were not previously treated with a KRAS G12C inhibitor, according to a news release from the drug’s developer, Revolution Medicines.1

Support for the agency’s decision is based on results from the phase 1 RMC-6291-001 trial (NCT05462717) evaluating the monotherapy in patients with advanced KRAS G12C-mutant solid tumors. According to the news release, the agent exhibited competitive antitumor activity, which included compelling objective response rate (ORR) and progression-free survival (PFS) data, as well as differentiated safety and tolerability outcomes.

“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-mutant] lung cancer,” Mark A. Goldsmith MD, PhD, chief executive officer and chairman of Revolution Medicines, said in the news release on the FDA decision.1 “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.”

Investigators in the international, single-arm, phase 1 dose-escalation and dose-expansion trial treated patients with escalating doses of elironrasib monotherapy until disease progression per RECIST v1.1 criteria, unacceptable toxicity, or other discontinuation criteria.2 Patients with KRAS G12C-mutant NSCLC, colorectal cancer, and pancreatic ductal adenocarcinoma were included, as well as those with other advanced solid tumors. Elironrasib was given as an oral tablet once or twice daily.

The coprimary end points of the trial were adverse effects and dose-limiting toxicities observed within the first 21 days, or first cycle, of study treatment. Secondary end points included maximum observed blood concentration, time to reach maximum blood concentration, area under the blood concentration time curve, elimination half-life, ORR, duration of response, disease control rate, time to response, and PFS.

Developers engineered elironrasib to selectively and covalently bond to an oncogenic RAS(ON) form of the RAS G12C variant observed in approximately 12% of NSCLC cases. They are conducting evaluations of the agent as a monotherapy and as part of combination therapies in numerous settings. Currently, no RAS-targeted inhibitors have full FDA approval to treat patients with KRAS G12C-mutant NSCLC.

According to an article published in Cancers, direct quantification of drug-bound KRAS G12C found in tumor biopsies could be afforded through KRAS G12C inhibition.3

Patients 18 years and older with pathologically documented, locally advanced or metastatic KRAS G12C-mutant solid tumor malignancies not amenable to curative surgery who were previously treated with standard-of-care therapies, intolerant to standard-of-care therapies, or ineligible for standard-of-care anticancer treatment were eligible for enrollment on the study. Additionally, patients must have had an ECOG performance score of 0 to 1 and adequate organ function to undergo enrollment. Those previously treated with a KRASG12C(OFF) inhibitor were permitted to enroll in the dose-escalation portion of the study.

Those ineligible for study enrollment included those with primary central nervous system metastases, active brain metastases, or those with absorption-impacting impairments of gastrointestinal function. Additionally, patients who had undergone major surgical procedures within 28 days of treatment, non–study-related minor procedures within 7 days of treatment, or prior therapy with a KRASG12C(OFF) inhibitor were excluded from trial participation.

References

1. Revolution Medicines announces FDA breakthrough therapy designation for elironrasib. News release. Revolution Medicines. July 23, 2025. Accessed July 24, 2025. https://tinyurl.com/k3xxd223
2. Dose escalation and dose expansion study of RMC-6291 monotherapy in subjects with advanced KRASG12C mutant solid tumors. ClinicalTrials.gov. Updated November 7, 2024. Accessed July 24, 2025. https://tinyurl.com/2v62ysvm
3. Reita D, Pabst L, Pencreach E, et al. Direct targeting KRAS mutation in non-small cell lung cancer: focus on resistance. Cancers. 2022;14(5):1321. doi:10.3390/cancers14051321