Elironrasib, a novel RAS G12C–selective tri-complex inhibitor, demonstrated initial clinical activity and a differentiated safety profile in heavily pretreated patients with non–small cell lung cancer (NSCLC) and KRAS G12C mutations, according to findings from a phase I trial presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Abstract LB-B024).
“This study illustrates how mechanism-driven drug design can overcome resistance. If the findings are borne out in larger trials, this approach could offer a new therapeutic paradigm for patients with a KRAS G12C mutation, not only in lung cancer but potentially across a range of solid tumors with the same alteration,” stated presenting study author Bruna Pellini, MD, Assistant Member of the Department of Thoracic Oncology at the Moffitt Cancer Center and Research Institute.
Rationale and Study Methods
Patients with KRAS G12C–mutant NSCLC who are treated with a first-generation KRAS G12C inhibitor ultimately experience disease progression. Typical resistance mechanisms enhance RAS pathway oncogenic flux via increased levels of the KRAS G12C protein, upstream RTK activation, and/or switch II binding pocket mutations in KRAS G12C.
Elironrasib (formerly RMC-6291) is a novel agent with a distinct mechanism of action from that of the first-generation KRAS G12C inhibitors, as it directly inhibits RAS(ON) G12C in its GTP-bound active form. In preclinical models, elironrasib was able to induce regression of tumors resistant to prior KRAS G12C inhibitors.
“Available KRAS G12C inhibitors target the inactive form of the KRAS protein, its GDP-bound ‘OFF’ state,” explained Dr. Pellini. “Our team wanted to see whether targeting the active, GTP-bound form of KRAS G12C—it’s ‘ON’ state—would help patients overcome resistance to the first-generation KRAS G12C inhibitors.”
The phase I RMC-6291-001 trial explored the use of multiple dose levels of elironrasib in patients with KRAS G12C–mutant NSCLC. The dose of 200 mg of elironrasib administered orally twice daily was selected for further evaluation based on pharmacokinetic, safety/tolerability, and efficacy data.
Key Study Findings
A total of 24 heavily pretreated patients were given the 200-mg twice-daily dose of elironrasib. The confirmed objective response rate was 42% (95% confidence interval [CI] = 22%–63%), and the disease control rate was 79% (95% CI = 58%–93%). The median duration of response was 11.2 months (95% CI = 5.9 months to not evaluable). The median progression-free survival was 6.2 months (95% CI = 4–10 months), and the median overall survival was not yet reached, but the 1-year overall survival rate was 62% (95% CI = 40%–78%).
“While this study is too small, and it is too early to draw any definitive conclusions, these results provide excellent signals,” Dr. Pellini said.
At baseline, 88% of patients had KRAS G12C alterations detectable by circulating tumor DNA. Seven of these patients harbored additional RTK and/or upstream MAPK pathway alterations at baseline, and five of the seven achieved a partial response, whereas the remaining two achieved stable disease.
“Responses in these patients, whose tumors had co-alterations of significance that are known to reactivate RAS signaling despite prior KRAS G12C inhibition, suggest elironrasib could potentially remain active even in the presence of these unique mechanisms that drive high levels of GTP-bound KRAS G12C,” Dr. Pellini said.
The majority of treatment-related adverse events were grade 1 or 2, and the most common events of any grade were diarrhea in 29% of patients, nausea in 21%, abdominal pain in 13%, and peripheral edema in 13%. Grade 3 events were reported in 8% of patients, and no grade 4 or 5 events were reported. Dose reduction because of treatment-related adverse events was required in two patients, but no dose discontinuations were required. The mean dose intensity was 93%.
Disclosure: The study was supported by Revolution Medicines. Dr. Pellini has received research support from BMS, the BMS Foundation/the Robert A. Winn Diversity in Clinical Trials Awards Program, and Merck; speaker honoraria from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Foundation Medicine, Regeneron, and OncoHost; and travel support from BMS, MSD, Gilead Sciences, and Regeneron. Dr. Pellini has also done consulting/advisory board work with AstraZeneca, AbbVie, Bayer, BMS, Catalyst Pharmaceuticals, Gilead Sciences, Guardant Health, Foundation Medicine, Illumina, Regeneron, Merus, and OncoHost, and is a steering committee member for BMS. For full disclosures of the other study authors, visit aacr.org.
