Zoldonrasib Shows Durable Responses in Previously Treated KRAS G12D-Mutant NSCLC
Updated phase I data showed zoldonrasib produced a 52% confirmed objective response rate and 93% disease control rate in previously treated KRAS G12D-mutant NSCLC. No grade 4 or higher treatment-related adverse events were observed at the recommended phase II dose.
The investigational KRAS G12D inhibitor zoldonrasib showed evidence of clinical activity and a favorable safety profile in patients with previously treated non-small cell lung cancer whose tumors harbored a KRAS G12D mutation, according to an updated phase I trial analysis presented at the AACR Annual Meeting 2026. Based on early trial observations in this patient population, zoldonrasib received FDA Breakthrough Therapy designation in January 2026.
Safety and efficacy of zoldonrasib are being tested in a phase I clinical trial in patients with KRAS G12D-mutant solid tumors who have received at least one prior line of treatment. In the most recent analysis, safety and tolerability were assessed in 40 trial participants with NSCLC who had received prior therapies and were treated at the recommended phase II dose of 1,200 mg once daily. No grade 4 or higher treatment-related adverse events were observed. Grade 3 treatment-related adverse events were reported in 13% of patients and included diarrhea and anemia. Treatment-related adverse events led to dose interruptions in 15% of patients, dose reductions in 3% of patients, and dose discontinuations in 5% of patients.
Clinical efficacy was evaluated in 27 patients who received the recommended phase II dose and who had been previously treated with immune checkpoint inhibitor therapy and platinum-based chemotherapy, concurrent or sequential, but not with docetaxel. In this subgroup, investigators reported a confirmed objective response rate of 52% and a disease control rate of 93%. Median duration of response was not estimable, median progression-free survival was 11.1 months, and median overall survival was not reached. The overall survival rate at 12 months was 73%.
No RAS-targeted therapy is currently available for patients whose tumors harbor KRAS G12D mutations. These mutations are found approximately in 4% of patients with NSCLC and are also present in a substantial portion of patients with pancreatic cancer and other gastrointestinal cancers, among others. Zoldonrasib is an oral, G12D-selective tri-complex RAS(ON) inhibitor that forms a ternary complex with KRAS and prevents KRAS from engaging and activating key downstream effector proteins involved in cell survival and growth.
The study was funded by Revolution Medicines. Additional ongoing studies will help further define zoldonrasib’s potential benefit in KRAS G12D-mutant NSCLC.