FDA Grants Breakthrough Status to Zoldonrasib in Lung Cancer

Revolution Medicines announced in a news release that the U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation to zoldonrasib for adult patients with KRAS G12D-mutated locally advanced or metastatic non-small cell lung cancer whose disease has progressed after treatment with anti-PD-1 or PD-L1 therapy and platinum-based chemotherapy, a step intended to speed development of a potential new targeted option for a group of patients with limited treatment choices.

The designation applies to zoldonrasib, an investigational RAS(ON) G12D-selective inhibitor, and reflects the FDA’s assessment that early clinical evidence suggests the therapy may offer meaningful improvement for patients with this specific genetic mutation in non-small cell lung cancer.

“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 cancers, which currently lack any approved targeted therapies,” Dr. Mark A. Goldsmith, chief executive officer and chairman of Revolution Medicines, said in the news release.

Main Data That Support the Findings

The FDA’s decision is based on results from the monotherapy cohort of the phase 1 RMC-9805-001 clinical trial, which is evaluating zoldonrasib in patients with advanced solid tumors driven by KRAS G12D mutations. According to the company, data from this cohort showed a robust clinical profile that included encouraging antitumor activity along with acceptable safety and tolerability.

Breakthrough therapy designation is reserved for investigational treatments for serious conditions when preliminary clinical evidence indicates the potential for substantial improvement on a clinically significant endpoint compared with available therapies. In this case, the FDA determined that the early findings from the phase 1 trial were sufficient to support the designation for patients with previously treated KRAS G12D-mutated non-small cell lung cancer.

Revolution Medicines stated that this is the first breakthrough therapy designation granted to an investigational drug that specifically targets the KRAS G12D mutation in non-small cell lung cancer. The company also noted that zoldonrasib is its third RAS(ON) inhibitor to receive this designation, following earlier recognitions for other agents in its pipeline.

KRAS G12D mutations represent a subset of non-small cell lung cancer for which there are currently no approved targeted therapies. The designation highlights the unmet medical need for patients whose cancers are driven by this mutation and who have already received standard treatments such as immunotherapy and platinum-based chemotherapy.

What are the Trial Details?

The phase 1 RMC-9805-001 trial is studying zoldonrasib in patients with advanced KRAS G12D solid tumors. The breakthrough therapy designation specifically draws on findings from the monotherapy cohort, in which zoldonrasib is given alone rather than in combination with other treatments.

Zoldonrasib is described as a tri-complex inhibitor that binds to cyclophilin A, forming a complex that selectively recognizes and inhibits the active, oncogenic KRAS G12D(ON) mutant. By targeting the active form of the mutated protein, the therapy is designed to interfere with cancer-driving signaling pathways associated with KRAS G12D.

In addition to the monotherapy approach, Revolution Medicines is evaluating zoldonrasib in combination regimens across multiple tumor types and different lines of therapy, though the breakthrough therapy designation announced applies to its use in previously treated non-small cell lung cancer with KRAS G12D mutations.

Non-small cell lung cancer accounts for approximately 80% to 85% of all lung cancers, with more than 197,000 people diagnosed each year in the United States. KRAS G12D is reported as the most common oncogenic driver across human cancers and is present in about 4% of non-small cell lung cancer cases, underscoring the potential relevance of a therapy aimed at this mutation.

What is the Safety of Zoldonrasib?

Safety and tolerability were key components of the data reviewed by the FDA. Revolution Medicines reported that the monotherapy cohort of the phase 1 trial demonstrated an acceptable safety and tolerability profile, supporting continued clinical development of zoldonrasib.

While detailed rates of side effects were not disclosed in the announcement, the company emphasized that the overall safety findings, alongside signs of antitumor activity, contributed to the FDA’s decision to grant the designation.

Breakthrough therapy designation does not mean that a drug is approved or that its risks are fully known, but it does allow for more frequent interactions with the FDA and the possibility of an expedited review process as development continues.

The company stated that it will continue to study zoldonrasib in clinical trials to further evaluate its safety and effectiveness in patients with KRAS G12D-mutated cancers, including those with non-small cell lung cancer who have already received prior standard therapies.

Reference

1. “Revolution Medicines Announces FDA Breakthrough Therapy Designation for Zoldonrasib.” News Release. Revolution Medicines. Jan 8, 2026.

Editor's note: This article is for informational purposes only and is not a substitute for professional medical advice, as your own experience will be unique. Use this article to guide discussions with your oncologist. Content was generated with AI, reviewed by a human editor, but not independently verified by a medical professional.

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