Zoldonrasib Earns FDA Breakthrough Therapy Status in KRAS G12D-Mutant NSCLC

The FDA has granted breakthrough therapy designation (BTD) to zoldonrasib (RMC-9805), a RAS(ON) G12D-selective inhibitor, in KRAS G12D-mutated, locally advanced or metastatic non–small cell lung cancer (NSCLC) previously treated with anti–PD-1/PD-L1 therapy and platinum-based chemotherapy.¹

Zoldonrasib is a potent, orally bioavailable tri-complex inhibitor that binds to cyclophilin A. Upon binding, it inhibits the active form of the RAS G12D protein by locking it into an inactive state.

The designation marks a crucial milestone in the agent’s development, as it recognizes the encouraging activity and potential clinically meaningful benefit over current treatment options as demonstrated by preliminary clinical data.

“The [BTD] 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 cancers, which currently lack any approved targeted therapies,” said Mark A. Goldsmith, MD, PhD, CEO and chairman of Revolution Medicines, in a news release.¹ “This recognition expands upon prior designations for the RAS(ON) multiselective 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.”

Supporting Phase 1 Data

The BTD is supported by preliminary data from the ongoing multicenter phase 1 RMC-9805-001 study (NCT06040541) evaluating the safety, tolerability, and preliminary efficacy of zoldonrasib as monotherapy in patients with advanced solid tumors harboring KRAS G12D mutations, including NSCLC, colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC).²

Encouraging initial antitumor activity and safety were reported with zoldonrasib monotherapy.³ As of December 2, 2024, 211 patients with KRAS G12D-mutant solid tumors received 5 escalating dose levels of zoldonrasib ranging from 150 to 1200 mg daily, with the recommended phase 2 dose (RP2D) established as 1200 mg daily. The objective response rate among patients with NSCLC (n = 18) who received the RP2D was 61% (95% CI, 36%–83%) with a median time of 1.4 months (range, 1.2–2.8) to onset of initial response. The disease control rate was 89% (95% CI, 65%–99%).

Further, the safety profile was deemed acceptable, with the most common treatment-related adverse events (TRAEs) being nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%), primarily grade 1 or 2 in severity.

Efficacy signals and favorable safety have likewise been reported in other studied indications, namely PDAC, according to a 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium presentation.

In a separate treatment arm of the study, zoldonrasib has been paired with daraxonrasib to evaluate the agent’s performance as combination therapy. Recruitment for the phase 1 study is ongoing, with a planned total enrollment of 604 patients. Patients are included if they have progressed on or shown intolerance to prior standard therapy.

REFERENCES

1. Revolution Medicines announces FDA breakthrough therapy designation for zoldonrasib. News release. January 8, 2026. Accessed January 8, 2026. https://tinyurl.com/bdd2j788

2. 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

3. Arbour KC, Tawee T, Yaeger R, et al. Abstract CT019: 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_Supplement_2):CT019-CT019. doi:10.1158/1538-7445.am2025-ct019