Zoldonrasib Earns FDA Breakthrough Therapy Designation in KRAS G12D+ NSCLC

The FDA has granted breakthrough therapy designation to zoldonrasib (RMC-9805), an investigational RAS(ON) KRAS G12D inhibitor, as a treatment for adults with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring KRAS G12D mutations who have previously received anti–PD-(L)1 treatment and platinum-containing chemotherapy, according to a press release from the developer, Revolution Medicines, Inc.¹

Supporting data for the breakthrough therapy designation came from the monotherapy cohort of the phase 1 RMC-9805-001 study (NCT06040541), in which investigators are evaluating zoldonrasib among patients with different KRAS G12D-mutated solid tumors. Investigators previously presented data from the NSCLC portion of the trial at the 2025 American Association for Cancer Research Annual Meeting (AACR).²

As of the data cutoff date of December 2, 2024, among 18 evaluable patients with NSCLC who received zoldonrasib at 1200 mg once daily, the objective response rate (ORR) was 61% (n = 11). Additionally, data showed a disease control rate (DCR) of 89% (n = 16).

At the time of analysis, zoldonrasib demonstrated a safety profile that was comparable with previous reports of the agent in pancreatic cancer among 90 patients with solid tumors. The most common treatment-related adverse effects (TRAEs) included nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%). Grade 3 TRAEs occurred in 2% of patients, which resolved following dose interruption.

“The breakthrough therapy designation for zoldonrasib, our RAS(ON) G12D-selective covalent inhibitor—the first ever granted for an investigational drug specifically targeting the RAS G12D mutation—underscores the significant unmet need for patients with [KRAS G12D-mutated] cancers, which currently lack any approved targeted therapies,” Mark A. Goldsmith, MD, PhD, chief executive officer and chairman at Revolution Medicines, stated in the press release.¹ “This recognition expands upon prior designations for the RAS(ON) multi-selective inhibitor daraxonrasib [RMC-6236] 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.”

Developers designed zoldonrasib as a tri-complex inhibitor directed towards cyclophilin A, which helps to selectively recognize and inhibit the oncogenic RAS G12D(ON) mutation. Assessment of the novel agent as a monotherapy and in combnination with other treatments is underway across several types of tumors and lines of therapy.

Investigators of the multicenter, open-label phase 1/1b RMC-9805-001 trial are evaluating the safety, tolerability, pharmacokinetics, and preliminary activity of zoldonrasib across part 1, a dose-exploration phase, and part 2, a dose-expansion phase.³ Patients will be assigned to receive zoldonrasib alone or in combination with daraxonrasib, both administered as oral tablets.

The trial’s primary end points include AEs and dose-limiting toxicities. Secondary end points include ORR, duration of response, DCR, time to response, progression-free survival, maximum observed blood concentration of zoldonrasib, and half-life of zoldonrasib.

Patients 18 years and older with pathologically confirmed locally advanced or metastatic solid tumors harboring a KRAS G12D mutation and progression on or intolerance of prior standard therapy are eligible for enrollment on the trial. Other eligibility criteria include having an ECOG performance status of 0 or 1 and adequate organ function.

Those with primary central nervous system (CNS) tumors, known or suspected leptomeningeal or active brain metastases or spinal compression, or known or suspected impairment of gastrointestinal function that may impact the ability to absorb or swallow oral therapy are ineligible for enrollment on the trial. Patients are also unable to enroll if they have prior treatment with an investigational KRAS G12D inhibitor, pan- or multi-RAS inhibitor, or any direct RAS-targeted therapy.

References

1. Revolution Medicines announces FDA breakthrough therapy designation for zoldonrasib. News release. Revolution Medicines, Inc. January 8, 2026. Accessed January 8, 2026. https://tinyurl.com/2nwac6j9
2. Revolution Medicines presents initial data from zoldonrasib (RMC-9805) study in patients with KRAS G12D mutant non-small cell lung cancer at the 2025 AACR Annual Meeting. News release. Revolution Medicines, Inc. April 27, 2025. Accessed January 8, 2026. https://tinyurl.com/28tmwft6
3. Study of RMC-9805 in participants with KRAS G12D-mutant solid tumors. ClinicalTrials.gov. Updated August 28, 2025. Accessed January 8, 2026. https://tinyurl.com/bdzhy8mv