The FDA has granted breakthrough therapy designation to zoldonrasib (RMC-9805-001) for the treatment of adult patients with KRAS G12D–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC) who have previously received anti–PD-1/PD-L1 therapy and platinum-based chemotherapy.1
Zoldonrasib Receives BTD in NSCLC: Key Takeaways
- The FDA has granted breakthrough therapy designation to zoldonrasib for the treatment of adult patients with KRAS G12D–mutated locally advanced or metastatic NSCLC who have previously received anti–PD-1/PD-L1 therapy and platinum-based chemotherapy.
- Patients with NSCLC who received zoldonrasib at 1200 mg daily (n = 18) experienced an ORR of 61%, a DCR of 89%, and a median TTR of 1.4 months (range, 1.2-2.8).
- The agent demonstrated acceptable safety and tolerability in this patient population.
The designation is supported by data from the monotherapy cohort of the phase 1 RMC-9805-001 trial (NCT06040541), which examined the RAS(ON) G12D-selective inhibitor in patients with advanced KRAS G12D–mutated solid tumors. Findings from RMC-9805-001 presented during the 2025 American Association for Cancer Research AACR Annual Meeting demonstrated that patients with NSCLC who received zoldonrasib at 1200 mg daily (n = 18) experienced an overall response rate (ORR) of 61%. The disease control rate (DCR) was 89%, and the median time to response (TTR) was 1.4 months (range, 1.2-2.8).2
“The breakthrough therapy designation for zoldonrasib, our RAS(ON) G12D-selective covalent inhibitor––the first ever granted for an investigational drug specifically targeting the KRAS G12D mutation––underscores the significant unmet need for patients with KRAS G12D cancers, which currently lack any approved targeted therapies,” Mark A. Goldsmith, MD, PhD, CEO and chairman of Revolution Medicines, stated in a news release.1 “This recognition expands upon prior designations for the RAS(ON) multi-selective inhibitor daraxonrasib and G12C-selective inhibitor elironrasib, further recognizing the promise of our first 3 clinical-stage RAS(ON) inhibitors as potentially transformative therapies for people living with RAS-addicted cancers.”
Zoldonrasib is a tricomplex inhibitor that binds to cyclophilin A. This binding creates a complex that selectively recognizes and inhibits the active, oncogenic RAS G12D(ON) mutant. The agent is being examined as monotherapy and a combination component across multiple tumor types and lines of therapy.
What were the key design characteristics of RMC-9805-001?
RMC-9805-001 was an open-label, multicenter study that enrolled adult patients with KRAS G12D–mutated solid tumors.3 To be eligible, patients had to have received, and experienced disease progression on or been intolerant to, prior standard therapy (including targeted therapy) appropriate for tumor type and stage. They also had to have an ECOG performance status of 0 or 1 and adequate organ function.
The study included monotherapy and combination arms, both with dose exploration and expansion components. Patients in the combination arm also received daraxonrasib (RMC-6236); both agents were administered orally.
The primary end point was safety, measured by the incidence of adverse effects (AEs) and dose-limiting toxicities. Secondary end points included ORR, DCR, progression-free survival, TTR, duration of response, and pharmacokinetic measures.
What were the safety data?
The median time on treatment was 2.6 months (range, 1.3-8.0).2 In terms of safety, patients who received zoldonrasib at 1200 mg daily (n = 90) experienced any-grade treatment-related AEs (TRAEs) at a rate of 74%. TRAEs leading to dose reduction (4%), interruption (9%), and discontinuation (1%) were all reported. The median dose intensity was 98%. Notably, no grade 4 or 5 TRAEs or serious AEs were reported.
Any-grade TRAEs that occurred in at least 10% of patients included nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%); diarrhea was the only grade 3 TRAE among these events. Other select any-grade TRAEs included increased aspartate aminotransferase (8%) and alanine aminotransferase (7%) levels, as well as stomatitis/mucositis (1%).
References
- Revolution Medicines announces FDA breakthrough therapy designation for zoldonrasib. News release. Revolution Medicines, Inc. January 8, 2026. Accessed January 8, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy-1
- Arbour KC, Tawee T, Yaeger R, et al. Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors. Cancer Res. 2025;85(8 suppl 2):CT019. doi:10.1158/1538-7445.AM2025-CT019
- Study of RMC-9805 in participants with KRAS G12D–mutant solid tumors. ClinicalTrials.gov. Updated August 28, 2025. Accessed January 8, 2026. https://clinicaltrials.gov/study/NCT06040541
