The investigational KRAS G12D inhibitor zoldonrasib had a favorable safety profile and induced antitumor activity in patients with KRAS G12D–mutated non–small cell lung cancer (NSCLC) who were previously treated with chemotherapy and immunotherapy, according to preliminary findings from an ongoing phase I study presented at the American Association for Cancer Research (AACR) Annual Meeting 2026 (Abstract CT021).
“Targeting and overcoming KRAS G12D–driven cancers, including NSCLC, with next-generation KRAS inhibitors represents a major unmet need for our patients,” stated presenting author Jonathan W. Riess, MD, Professor of Medicine, Director of Thoracic Oncology, and Director of Early Phase Therapeutics at University of California (UC), Davis Comprehensive Cancer Center.
Background and Study Methods
Two KRAS inhibitors have already been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with KRAS G12C–mutated NSCLC. However, there are currently no RAS-targeted therapies available for patients with NSCLC harboring a KRAS G12D mutation.
Zoldonrasib is an oral G12D-selective tricomplex RAS(ON) inhibitor that is currently being studied in a phase I clinical trial of patients with solid tumors harboring KRAS G12D mutations who have received at least one prior line of therapy. The agent forms a ternary complex with KRAS, which prevents KRAS from activating downstream effector proteins for cell growth and survival.
In the study, patients received escalating doses of zoldonrasib from 150 mg to 1200 mg once-daily or 300 mg to 600 mg twice-daily. The 1,200 mg once-daily schedule was set as the recommended phase II dose for the NSCLC subgroup. A total of 40 patients were treated at this dose.
Prior results from this study showed encouraging safety and efficacy data in a NSCLC subgroup, which led to the agent receiving an FDA Breakthrough Therapy designation in January 2026.
Key Findings
Patients (n = 40) were followed for a median of 13.1 months (range, 9.1–19.9 months) for safety and efficacy.
Among 27 patients who had received a prior immune checkpoint inhibitor and platinum chemotherapy, either concurrently or sequentially, although who were not previously exposed to docetaxel, the confirmed objective response rate was 52% (95% confidence interval [CI] = 32%–71%) and the disease control rate was 93% (95% CI = 76%–99%).
The median duration of response in this group was not estimable (95% CI = 8.3 months to not estimable). The median progression-free survival was 11.1 months (95% CI = 5.3 to not estimable), and the median overall survival was not reached. At 12 months, the overall survival rate was 73%.
Among all patients with KRAS G12D–mutant NSCLC treated at the recommended phase II dose, the most common treatment-related adverse events (≥ 15%) were nausea (43%), vomiting (33%), diarrhea (30%), and rash (18%); most treatment-related events were grade 1 (58%) or grade 2 (20%). Grade 3 treatment-related adverse events were reported in 13% of patients, including diarrhea (3%) and anemia (3%) most commonly. No grade 4 or 5 events were observed.
Treatment-related events led to dose interruptions in 15% of patients, dose reductions in 3% of patients, and dose discontinuations in 5%. The mean relative dose intensity was 94%.
"Zoldonrasib demonstrated a favorable safety and tolerability profile, a promising response rate with durable responses, and an encouraging rate of disease control in patients whose lung cancer had progressed on prior chemotherapy and immunotherapy,” said Dr. Riess. “Our findings suggest that KRAS G12D–mutated lung cancer is treatable with promising efficacy of zoldonrasib.”
“While the safety signals and preliminary antitumor activity are encouraging, the results are based on a small sample size,” added Dr. Riess. “This study provides a preliminary encouraging signal of zoldonrasib activity in KRAS G12D–mutant NSCLC. Additional ongoing studies will help further define zoldonrasib’s potential benefit in this context.”
DISCLOSURES: The study was funded by Revolution Medicines. Dr. Riess reported honoraria for advisory boards and consulting from Daiichi Sankyo, Bristol Myers Squibb, Janssen, Regeneron, Genentech, Merck, Pfizer, GSK, Replimune, OncoHost, ArriVent, Nuvation Bio, Nuvalent, Taiho Pharmaceuticals, Verastem, Boehringer Ingelheim, AstraZeneca, Foundation Medicine, and Revolution Medicines. UC Davis Comprehensive Cancer Center received research funding from AstraZeneca, Novartis, Merck, Revolution Medicines, Prelude Therapeutics, BlossomHill Therapeutics, Summit Pharmaceuticals, Pfizer, Nuvalent, IO Biotech, Boehringer Ingelheim, Bicycle Therapeutics, Janssen, and ArriVent. For full disclosures of the other study authors, visit abstractsonline.com.
