AT the AACR 2025 Annual Meeting in Chicago, new data presented on the investigational agent zoldonrasib showed encouraging clinical activity in patients with non-small cell lung cancer (NSCLC) harboring the KRAS G12D mutation. These results mark a potential breakthrough for a patient population historically underserved by targeted therapies.
KRAS is among the most commonly mutated genes in cancer, with the G12D variant accounting for roughly 4% of NSCLC cases. While KRAS G12C mutations have two FDA-approved therapies, no targeted treatments are currently available for KRAS G12D-mutated tumors. Patients are typically treated with chemotherapy and immune checkpoint inhibitors, but often see limited benefit and poor outcomes.
Zoldonrasib, a novel oral RAS(ON) tri-complex inhibitor, specifically targets the active conformation of KRAS G12D. This mechanism contrasts with KRAS G12C inhibitors, which bind the inactive form and may allow cancer cells to develop resistance more readily. Presenting the findings, Dr Kathryn Arbour of Memorial Sloan Kettering Cancer Center emphasized the drug’s unique potential to delay or prevent resistance.
In a phase I trial, 211 patients with KRAS G12D-mutated solid tumors received zoldonrasib, including 90 treated at the recommended phase II dose of 1200 mg daily. Among 18 patients with NSCLC eligible for efficacy analysis, 61% achieved an objective response, and 89% experienced disease control—substantially higher than the typical 10–15% response seen with standard chemotherapy like docetaxel.
The treatment was well tolerated, with no grade 4 or 5 treatment-related adverse events. Most side effects, including nausea, diarrhea, and fatigue, were low-grade and manageable. Importantly, side effects commonly seen with other RAS inhibitors—such as rash and liver enzyme elevations—were not observed.
“These data represent a substantial advance for patients with KRAS G12D-mutated lung cancer,” Dr Arbour said. She highlighted the need for longer follow-up and larger studies, but noted that the early findings provide optimism for more effective treatment options.
Reference:
American Association for Cancer Research. Oral Investigational Agent Zoldonrasib Elicits Objective Responses in Patients With KRAS G12D-mutated Lung Cancer. 2025. Available at: https://aacr.ent.box.com/s/6yarrl35ziyqz1jveylbncghegkca59p. Last accessed: 1 May 2025.
