AACR 2026: Zoldonrasib Shows Promising Responses in KRAS G12D–Mutated Lung Cancer
Posted: Monday, May 4, 2026
The investigational KRAS inhibitor zoldonrasib is emerging as a promising targeted therapy for patients with KRAS G12D–mutated non–small cell lung cancer (NSCLC), a population with limited treatment options. At the American Association for Cancer Research (AACR) Annual Meeting 2026, Jonathan W. Riess, MD, of the Davis Comprehensive Cancer Center, University of California, presented the findings of an updated trial analysis highlighting the drug’s clinical activity and tolerability. The study was conducted to address a major unmet need, as KRAS G12D mutations—present in about 4% of NSCLC cases—currently lack approved targeted therapies.
Study Details
The data come from an ongoing phase I clinical trial evaluating zoldonrasib, a G12D-selective RAS(ON) inhibitor. Patients with KRAS G12D–mutant solid tumors received escalating doses, with 1,200 mg once daily identified as the recommended phase II dose. Safety analyses included 40 patients with NSCLC who had received a median of two prior lines of therapy, while efficacy analyses focused on 27 patients previously treated with both immune checkpoint inhibitors and platinum-based chemotherapy. Tumor responses were assessed every 6 weeks for the first 24 weeks and every 9 weeks thereafter, and adverse events were carefully monitored. Median follow-up was 13.1 months (interquartile range = 9.1–19.9 months).
Key Takeaways
Most treatment-related adverse events were low-grade, with common side effects including nausea (43%), vomiting (33%), diarrhea (30%), and rash (18%). Grade 3 adverse events occurred in 13% of patients; no grade 4 or 5 events were reported. Dose modifications were infrequent, and the mean relative dose intensity remained high at 94%, indicating that most patients were able to maintain consistent treatment.
Among the 27 evaluable patients, the confirmed objective response rate was 52% and the disease control rate reached 93% (95% confidence interval [CI] = 76%–99%). Median progression-free survival was 11.1 months (95% CI = 5.3 to not estimable), while median duration of response and overall survival had not yet been reached at the time of analysis.
Despite the study’s limitations, including its small sample size and early-phase design, the results support further investigation in both monotherapy and combination settings. As Riess emphasized, “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. Our findings suggest that KRAS G12D-mutated lung cancer is treatable with promising efficacy of zoldonrasib.”
DISCLOSURE: The study was funded by Revolution Medicines. For full disclosures of the study authors, visit abstractsonline.com.
