Promising Results for Zoldonrasib in Treating KRAS G12D-Mutated Lung Cancer: Phase I Clinical Trial

In a recent breakthrough presented at the American Association for Cancer Research (AACR) Annual Meeting 2025, researchers reported encouraging responses of patients with KRAS G12D-mutated lung cancer to the experimental oral drug zoldonrasib. The study involved patients with previously treated non-small cell lung cancer (NSCLC) whose tumors harbored the KRAS G12D mutation, a genetic alteration that has historically lacked targeted therapies.

KRAS mutations are among the most common in various cancers, with G12D being a notable variant, representing approximately 4% of NSCLC cases. Unlike the more commonly targeted G12C mutation, which accounts for about 13% of NSCLC mutations and has approved treatments, the G12D mutation has been difficult to target. Patients with KRAS G12D-mutated NSCLC generally receive chemotherapy and immune checkpoint inhibitors but often show limited benefit, underscoring the need for new targeted options.

Zoldonrasib is a novel inhibitor designed to selectively target the active conformation of KRAS G12D. This mechanism distinguishes it from other KRAS inhibitors that typically aim to lock the protein in an inactive state, potentially delaying resistance. The phase I trial enrolled 211 patients with KRAS G12D-mutated solid tumors, with 90 receiving the recommended dose of 1,200 mg daily. Results showed the treatment was well tolerated; no high-grade (grade 4 or 5) adverse events were observed. Side effects such as nausea, diarrhea, and fatigue were common but manageable.

Efficacy data from a subset of 18 NSCLC patients demonstrated an objective response rate of 61% and a disease control rate of 89%, which is a significant improvement over the typical response to standard chemotherapy like docetaxel, which ranges from 10% to 15%. The safety profile and preliminary effectiveness suggest zoldonrasib could be a promising new therapeutic option for this hard-to-treat mutation.

While these initial findings are encouraging, researchers emphasize that larger studies with longer follow-up are essential to fully understand the clinical impact of zoldonrasib. Nonetheless, the ability to selectively target KRAS G12D with an oral, well-tolerated drug marks a notable advance in personalized cancer treatment, potentially changing the therapeutic landscape for patients with this mutation.