Zoldonrasib Shows Promising Activity in KRAS G12D+ NSCLC

Zoldonrasib (RMC-9805), an investigational RAS(ON) inhibitor, exhibited promising anti-tumor activity among patients with previously treated KRAS G12D-mutated non–small cell lung cancer (NSCLC), according to a presentation on findings from the phase 1/1b RMC-9805-001 study (NCT06040541) at the 2026 American Association for Cancer Research (AACR) Annual Meeting.

Following the meeting, presenting study investigator Jonathan Wesley Riess, MD, MS, spoke with CancerNetwork® about how these findings may support zoldonrasib as a potential therapeutic option in the field. After breaking down the novel agent’s mechanism of action, he detailed efficacy outcomes such as progression-free survival (PFS) and the overall response rate (ORR), as well as its “superb” safety profile in this patient population. Looking towards the future, Riess said that different initiatives may aim to evaluate zoldonrasib in combination with other targeted therapeutics like daraxonrasib (RMC-6236).

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

Riess is the director of Thoracic Oncology and an associate professor of medicine at UC Davis Comprehensive Cancer Center in Sacramento, California.

CancerNetwork: What was the background for this presentation focused on zoldonrasib among patients with NSCLC harboring KRAS G12D mutations?

Riess: Uncontrolled RAS(ON) signaling drives cells to an oncogenic state. Normally, this is a tightly regulated process under standard conditions where RAS(ON) proteins control cell growth. In the setting of RAS cancer mutations, there’s excessive RAS(ON) signaling that drives uncontrolled cell growth. There’s a number of KRAS mutations, mainly concentrated in G12, G13, and Q61. KRAS G12D is the most common oncogenic RAS mutation in human tumors. There are no approved targeted treatments for KRAS G12D. There are [options] for KRAS G12C in NSCLC. KRAS G12D frequency comprises about 40% of pancreatic adenocarcinoma, 15% of colorectal cancer, and 4% of NSCLC. Treatment options for the 4% of patients with NSCLC after progression on standard immunotherapy and chemotherapy are limited; you’re [typically] looking at second-line docetaxel with consideration of ramucirumab [Cyramza]. That often has substantial [adverse] effects [AEs] as well as low response rates, progression-free survival [PFS], and limited overall survival [OS].

What properties does zoldonrasib possess as a KRAS(ON) inhibitor that may differentiate it from other standards of care in the field?

[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.

What efficacy did zoldonrasib show in this patient population?

The efficacy population was 27 patients treated with prior immune checkpoint inhibitors and platinum-based chemotherapy. [Zoldonrasib] showed a 52% confirmed response rate in this population. This population was selected to provide the closest comparator to that second-line setting of patients who have progressed on platinum-based chemotherapy and [immunotherapy]. The ORR was 52%, and those were confirmed responses. The disease control rate was 93%. The median time to response was 1.4 months. The median duration of response was not reached. The median PFS was 11.1 months. The 12-month PFS rate was 48%. The median OS was not reached, with 73% of patients alive at 1 year.

What did the safety data show about zoldonrasib in this trial?

The safety population was 40 patients treated with zoldonrasib, and this was at the recommended phase 2 dose of 1200 mg daily. Safety was superb. There were no treatment-related grade 4 or 5 AEs or serious AEs that were reported. The main AEs were GI related and grade 1, which are typically mild and manageable, such as nausea, vomiting, and diarrhea. [Additionally,] 18% of patients had rash, but it was grade 1; again, mild.

Some of these KRAS inhibitors cause increases in liver enzymes, but that was only observed in 10% of patients and was grade 1. There were some grade 3 TRAEs, 1 patient with diarrhea, 1 patient with anemia, 2 patients with grade 3 blood creatine phosphokinase [changes], and 1 patient with grade 3 facial [nerve palsy]. Overall, it was extremely well tolerated.

The take-home message is the majority of AEs were GI related, grade 1, and very manageable. Just to give a sense of that, only 2 patients, 5%, needed to discontinue treatment. Only 1 patient, 3%, had a dose reduction, and the mean and median dose intensity was 94% and 97%, respectively. It was a very high delivery of dose intensity [with] mild and manageable AEs.

What are the next steps for researching zoldonrasib in NSCLC or other patient populations?

The main thing is this showed good evidence of preliminary activity and safety. There’s a larger study that’s in progress treating more patients. Then, there are combination strategies, including the multi-selective RAS inhibitor daraxonrasib in solid tumors, in terms of combining with zoldonrasib. [There are also] standard chemoimmunotherapy regimens for NSCLC and standard-of-care regimens for GI cancers.

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.