Encouraging activity and tolerability were observed among patients with KRAS G12D–mutated non-small cell lung cancer (NSCLC) who received treatment with zoldonrasib (RMC-9805), a novel oral RAS(ON) G12D inhibitor, according to findings from the phase 1/1b RMC-9805-001 study (NCT06040541) presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting.1
At a median follow-up of 13.1 months (range, 9.1-19.9) Patients who were treated with zoldonrasib at 1200-mg daily who received a prior immune checkpoint inhibitor and platinum-based chemotherapy without prior docetaxel (n = 27) achieved an overall response rate of 52% (95% CI, 32%-71%), and a disease control rate was 93% (95% CI, 76%-99%). The median time to response was 1.4 months (range, 1.2-4.0) and the median duration of response was not estimable (NE; 95% CI, 8.3-NE).
The median progression-free survival (PFS) was 11.1 months (95% CI, 5.3-NE) and the 12-month PFS rate was 48% (95% CI, 27%-66%). The median overall survival (OS) was NE (95% CI, NE-NE) and the 12-month OS rate was 73% (95% CI, 52%-86%). The 100% KRAS G12D variant allele frequency (VAF) clearance rate was 73% (n = 11 of 15) and 87% (n = 13 of 15) of patients experienced a minimum KRAS G12D VAF clearance of 50%.
“Zoldonrasib is an oral, potent, mutant-selective, covalent inhibitor of RAS(ON) G12D,” Jonathan Wesley Riess, MD, MS, the director of thoracic oncology and an associate professor of medicine at UC Davis Comprehensive Cancer Center in Sacramento, California, said during the presentation. “Zoldonrasib is well-tolerated and manageable with primarily grade 1 treatment-related adverse effects [TRAEs]. No grade 4 or 5 TRAEs were noted and zoldonrasib was able to be delivered with a high dose intensity.”
In January 2026, the FDA granted breakthrough therapy designation to zoldonrasib for the treatment of adult patients with KRAS G12D–mutated locally advanced or metastatic NSCLC who have been previously treated with anti-PD-1/PD-L1 therapy and platinum-based chemotherapy.2
How was the phase 1 study evaluating zoldonrasib in KRAS G12D–mutated NSCLC designed?
RMC-9805-001 enrolled patients with advanced solid tumors harboring KRAS G12D mutations.1 Patients were also required to have received prior standard therapy appropriate for tumor type and stage, an ECOG performance status of 0 or 1, and no active brain metastases.
During the dose-escalation phase, zoldonrasib was administered at 150 mg, 300 mg, 600 mg, 900 mg, or 1200 mg daily, or 300 mg, 450 mg, or 600 mg twice daily. The study also included a dose expansion and optimization portion in NSCLC and pancreatic ductal adenocarcinoma (PDAC).The key end points of the study included safety and tolerability, pharmacokinetics, and antitumor activity.
At baseline, the median age in the safety population (n = 40) was 66 years (range, 36-86). Most patients were female (57%), had an ECOG performance status of 1 (68%), were current/past smokers (55%), had stage IV disease at diagnosis (68%), and received 1 prior line of therapy (53%). The median number of prior anticancer therapies was 2 (range, 0-5).
What safety data for RMC-9805-001 were presented during the AACR Annual Meeting?
In terms of safety, any-grade TRAEs were reported in 90% of patients. The most common any-grade TRAEs that occurred in at least 10% of patients included nausea (43%), vomiting (33%), and diarrhea (30%). Grade 3 TRAEs were reported at a rate of 13% and included diarrhea (3%) and anemia (3%). No grade 4 or 5 TRAEs of serious AEs were reported. Dose interruptions (15%), reductions (3%), and discontinuations (5%) all occurred.
No dose-limiting toxicities were reported and the maximum tolerated dose of zoldonrasib was not reached. The recommended phase 2 dose of zoldonrasib was determined to be 1200 mg daily in PDAC and NSCLC.
“Preliminary safety and antitumor activity support the continuing development of zoldonrasib as a single agent and in combination with other therapies,” Riess said in his conclusion.
Disclosures: Riess received researcher/grant/contracts paid to institute from Merck, AstraZeneca, ArriVent, Boehringer Ingelheim, Novartis, Revolution Medicines, IO Biotech, Summit Pharmaceuticals, Nuvalent, Pfizer, Blossom Hill, and Prelude Therapeutics. He holds consulting/advisory board roles with ArriVent, Daiichi Sankyo, AstraZeneca, Pfizer, Regeneron, Catalyst, Janssen, BMS, Genentech, Amgen, GSK, Replimmune, Oncohost, Bicycle Therapeutics, Nuvalent, Taiho, Verastem, Merck, Boehringer Ingelheim, Natera, and Foundation Medicine. He received travel considerations from IO Biotech and Foundation Medicine.
References
- 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.
- Revolution Medicines announces FDA breakthrough therapy designation for zoldonrasib. News release. Revolution Medicines. January 8, 2026. Accessed April 20, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy-1
