How is Zoldonrasib Different From Other Therapies in KRAS G12D+ NSCLC?

Zoldonrasib (RMC-9805), a novel KRAS G12D RAS(ON) inhibitor, has demonstrated “promising activity” while being “very well tolerated” among patients with KRAS G12D-mutated non–small cell lung cancer (NSCLC), according to Jonathan Wesley Riess, MD, MS.

In a conversation with CancerNetwork^®, Riess discussed key takeaways from a presentation he gave at the 2026 American Association for Cancer Research (AACR) Annual Meeting about findings from the phase 1/1b RMC-9805-001 study (NCT06040541) evaluating zoldonrasib among those with KRAS G12D–mutated NSCLC. Among 27 evaluable previously treated patients who received zoldonrasib at 1200 mg once daily, the confirmed overall response rate was 52% (95% CI, 32%-71%), and the disease control rate was 93% (95% CI, 76%-99%). Additional data revealed a median progression-free survival (PFS) of 11.1 months (95% CI, 5.3-not evaluable), and a 12-month PFS rate of 48% (95% CI, 27%-66%).

Riess, the director of Thoracic Oncology and an associate professor of medicine at UC Davis Comprehensive Cancer Center in Sacramento, California, also outlined the novel agent’s mechanism of action and how its specificity for G12D may set it apart from other drugs.

Transcript:

[Zoldonrasib] is a KRAS G12D RAS(ON) inhibitor. It’s selective for G12D, and it’s an (ON) inhibitor. The (OFF) inhibitors bind to the GDP-inactive state of RAS. [Zoldonrasib] binds to the GTP-active state of RAS, and it is particular to G12D. What zoldonrasib does is form a tri-complex that sterically includes RAF interaction and inhibits RAS(ON) oncogenic activity and downstream signaling. Its main differentiating factor is, one, [being] specific for G12D. Two, it’s a RAS(ON) [inhibitor] binding to the GTP-bound form of RAS.

This is a very well tolerated drug that has promising activity with a good response rate and progression-free survival efficacy data in an area where there there’s a large unmet need and no approved targeted treatments, which is KRAS G12D-mutated NSCLC.

Reference

Riess J, Haura EB, Yaeger R, et al. Preliminary safety and clinical activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with previously treated KRAS G12D non-small cell lung cancer (NSCLC). Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract CT021.