Zoldonrasib Becomes the First Agent Found Effective Against KRAS G12D

Lung cancer remains a leading cause of cancer-related death worldwide.

• Among patients diagnosed with non-small cell lung cancer (NSCLC), approximately 15-20% have various KRAS mutations.

• Approximately 3-4% of all patients with NSCLC have a KRAS G12D mutation.

• Among patients with KRAS mutation-positive NSCLC , the proportion is approximately 15% (KRAS G12C is the most common subtype, followed by G12D and G12V).

KRAS G12D mutations are particularly common in never-smokers and make responses to current treatments challenging. Developing new options targeting KRAS G12D is therefore important.

Findings presented at AACR 2025 show that the next-generation agent zoldonrasib has produced highly promising results in KRAS G12D-mutated NSCLC.

Why Is KRAS G12D Difficult to Target?

Known by the code RMC-9805, zoldonrasib, in cancers carrying a KRAS G12D mutation has become one of the first mutant-selective targeted agents to demonstrate clinical activity. The G12D mutation was long considered “undruggable” because it remains in the active, GTP-bound conformation.

Among agents previously developed in this field, MRTX1133remained at the preclinical stage.

• BI-2865 and similar structure-based inhibitors did not reach clinical development.

• Pan-RAS inhibitorshad limited success against G12D despite their broad targets.

Zoldonrasibstood out as the first candidate capable of selectively and covalently binding active G12D-mutated RAS.

Overall, zoldonrasib is the targeted candidate that has achieved, for KRAS G12D, the first substantial clinical success to date.

Response Rates with Zoldonrasib

The study, “RMC-9805-001,” is an early-stage, multicenter phase 1 clinical trial.

In the interim analysis dated December 2, 2024, among patients carrying a KRAS G12D mutation, 28 patients with SCLC received zoldonrasib 1200 mg daily, with the following results:

• Objective response rate (ORR) was 61%.

• Disease control rate (DCR) reached a high level of 89%.

• Median time to response was only 1.4 months (range 1.2-2.8 months).

• Median time on treatment was 2.6 months (range 1.3-8 months).

These are among the most promising findings to date for KRAS G12D-mutated NSCLC.

Adverse Reactions

Zoldonrasib safety was examined in detail in a total of 90 patients:

• Most treatment-related adverse reactions (54%) were mild (grade 1).

• Moderate (grade 2) reactions occurred in 18%.

• Severe (grade 3) reactions occurred in only 2%.

• No Grade 4 or 5, described as life-threatening, adverse reactions occurred.

These findings supported selecting 1200 mg daily as the ideal zoldonrasib dose for phase 2 studies.

How Does Zoldonrasib Work?

Zoldonrasib is a mutant-selective inhibitor targeting active, GTP-bound RAS. It aims to inhibit growth and proliferation in tumors carrying KRAS G12D mutations.

Revolution Medicines, Inc. is the biotechnology company that developed it.

The approach previously produced encouraging pancreatic cancer findings, including 30% ORR and 80% DCR. Similar success in NSCLC now suggests potentially broad activity.

Study Details and Patient Profile

The overall study involved 211 patients with the following characteristics:

• Mean age: 62 (range 25-86 years)

• Male patients: 55%

• All had an ECOG performance status of 0-1; the proportion with a score of 1 was 70%.

• Mean number of previous cancer treatments: 2 (range 0-10)

The 28 patients with NSCLC taking 1200 mg daily had demographics similar to the overall population. In this subgroup, 86% had previously received platinum-based chemotherapy and immune checkpoint inhibitor treatment.

A Real-World Example from the Study

The study described a 36-year-old Asian woman who had never smoked and had KRAS G12D-mutated lung cancer progressing despite previous standard treatments. After starting zoldonrasib 1200 mg daily, she rapidly improved clinically. The first assessment showed a partial response that deepened over time, along with substantial improvement in cough and oxygen requirements.

Further Adverse Reaction Details

The most common reactions with zoldonrasib were:

• Nausea (33% mild, 6% moderate)

• Diarrhea (20% mild, 3% moderate, 1% severe)

• Vomiting (13% mild, 4% moderate)

• Skin rash (12% mild)

These were generally mild and did not substantially disrupt continued treatment.

What Comes Next?

Combination studies with other treatments are planned. Currently:

• Solid-tumor studies with daraxonrasib (RMC-6236),

• and phase 1/2 studies with standard treatments in lung and gastrointestinal cancers are ongoing.

When completed, these studies may establish zoldonrasib as a new option for many patients with KRAS G12D mutations.

Conclusion

These pioneering findings in KRAS G12D-mutated NSCLC could address an important unmet need. They again highlight personalized medicine's importance and may offer hope to a wider patient population through further research.