FDA Grants Breakthrough Therapy Designation to Daraxonrasib for KRAS G12X-Mutant Metastatic PDAC

FDA

The FDA has granted breakthrough therapy designation to daraxonrasib (RMC-6236), a direct RAS(ON) multi-selective inhibitor, for the treatment of patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) harboring KRAS G12X mutations.1

The designation was supported by findings from the phase 1 RMC-6236-001 trial (NCT05379985). Updated findings from the study presented at the 2025 Gastrointestinal Cancers Symposium showed that patients with second-line metastatic PDAC harboring KRAS G12X mutations treated with daraxonrasib at 300 mg per day (n = 22) achieved a median progression-free survival (PFS) of 8.8 months (95% CI, 8.5-not evaluable [NE]).2 Among those with broader RAS-mutated disease treated at the 300-mg dose (n = 37), the median PFS was 8.5 months (95% CI, 5.9-NE). For patients treated at daily doses ranging from 160 mg to 300 mg in the KRAS G12X–mutant population (n = 42) and RAS-mutant population (n = 57), the median PFS was 8.5 months (95% CI, 5.3-11.7) and 7.6 months (95% CI, 5.9-11.1), respectively.

Objective response rates (ORRs) at the 300-mg dose were 36% for patients in the KRAS G12X–mutant population and 27% in the RAS-mutant population. The respective disease control rates were 91% and 95%.

“This breakthrough therapy designation underscores the enormous need for new treatments for patients with pancreatic cancer and highlights the potentially important role the investigational drug, daraxonrasib, may have in helping patients living with this disease,” Mark A. Goldsmith MD, PhD, chief executive officer and chairman of Revolution Medicines, stated in a news release.1

Daraxonrasib is an oral, direct RAS(ON) multi-selective inhibitor that targets active, GTP-bound RAS to block its interaction with downstream effectors involved in oncogenic signaling. The agent is designed to inhibit a broad spectrum of KRAS mutations—specifically G12X, G13X, and Q61X.

The phase 1 study included patients at least 18 years of age with advanced solid tumors harboring KRAS G12X mutations, except for KRAS G12C mutations.2 Prior standard therapy was required, and patients were not allowed to have brain metastases.

Daraxonrasib was evaluated at daily doses ranging from 10 mg to 400 mg; the 160-mg, 220-mg, and 300-mg doses were explored for dose optimization and use in phase 3 study.

Daraxonrasib is now under investigation in the global phase 3 RASolute-302 study (NCT06625320), which is evaluating the agent vs standard-of-care chemotherapy in patients with previously treated metastatic PDAC.3 Eligible patients must have histologically or cytologically confirmed metastatic PDAC and have progressed following treatment with a 5-fluorouracil–based or gemcitabine-based regimen.

Patients need to have documented RAS-mutant or wild-type status, with RAS mutations defined as nonsynonymous mutations in KRAS, NRAS, or HRAS at codons G12, G13, or Q61. Measurable disease per RECIST 1.1 criteria and adequate organ function are also required.

Patients are being randomly assigned 1:1 to receive daraxonrasib or chemotherapy.

PFS and overall survival in the KRAS G12X-mutant population are serving as the study’s primary end points.

“We look forward to substantially completing enrollment of the RASolute 302 study this year to enable an expected readout in 2026, and should the results support it, working closely with the FDA and other regulatory agencies around the world to bring daraxonrasib to patients as quickly as possible,” Goldsmith said.

References

1. Revolution Medicines announces FDA breakthrough therapy designation for daraxonrasib in previously treated metastatic pancreatic cancer with KRAS G12 mutations. News Release. Revolution Medicines, Inc. June 23, 2025. Accessed June 27, 2025. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy
2. Garrido-Laguna I, Wolpin B, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2025, 43(suppl 4):722.doi:10.1200/JCO.2025.43.4_suppl.722
3. Phase 3 study of daraxonrasib (RMC-6236) in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) (RASolute 302). ClinicalTrials.gov. Updated May 21, 2025. Accessed June 27, 2025. https://www.clinicaltrials.gov/study/NCT06625320