Revolution Medicines Shares Early Zoldonrasib Data in KRAS G12D NSCLC at 2025 AACR
Revolution Medicines, Inc. a late-stage clinical oncology company committed to developing targeted therapies for patients with RAS-addicted cancers, today unveiled new clinical data on zoldonrasib (RMC-9805), a selective inhibitor targeting the RAS(ON) G12D mutation. The data, which were presented as part of the official press program at the American Association for Cancer Research (AACR) Annual Meeting in Chicago, Illinois, highlight the early-stage efficacy and tolerability of zoldonrasib as monotherapy in patients with KRAS G12D mutant non-small cell lung cancer (NSCLC). The findings were showcased in a late-breaking oral presentation on April 27, 2025, at 5:00 p.m. Central Time.
The data further confirm the clinical promise of zoldonrasib in targeting the KRAS G12D mutation, an area of significant unmet need. “We are excited to share these new clinical findings on zoldonrasib, an oral RAS(ON) G12D-selective inhibitor. These results demonstrate the compound’s acceptable safety profile and its encouraging initial antitumor activity in patients with non-small cell lung cancer,” remarked Mark A. Goldsmith, M.D., Ph.D., Chief Executive Officer and Chairman of Revolution Medicines.
“This progress, together with the previously reported tolerability and antitumor activity in patients with pancreatic ductal adenocarcinoma, strengthens the growing clinical evidence for the potential of zoldonrasib. These results encourage us to continue advancing its evaluation both as a monotherapy and in combination, as part of our ongoing commitment to developing innovative targeted therapies for patients with hard-to-treat cancers.”
Study Design and Methodology: Phase 1 Trial in Solid Tumors
The clinical data presented are part of the ongoing Phase 1 study, designated RMC-9805-001, which is a multicenter, open-label, dose-escalation, and dose-expansion trial designed to evaluate the safety, tolerability, and preliminary efficacy of zoldonrasib in patients with advanced solid tumors harboring the KRAS G12D mutation. The study aims to determine the recommended Phase 2 dose of zoldonrasib and assess its potential as a monotherapy for patients with this specific KRAS mutation, which is considered an important therapeutic target for a range of cancers, particularly lung and pancreatic cancers.
As of a data cutoff date of December 2, 2024, a total of 90 patients with solid tumors had received treatment with zoldonrasib at a dose of 1200 mg once daily (QD), which was identified as the recommended Phase 2 dose based on earlier study findings. The evaluation of safety and tolerability in this cohort demonstrated that zoldonrasib had an acceptable safety profile. The observed side effects were generally consistent with earlier reports from studies on zoldonrasib in pancreatic cancer patients, further supporting its overall safety and tolerability.
Safety Profile: Acceptable and Consistent with Prior Findings
The safety findings for zoldonrasib revealed that the most common treatment-related adverse events (TRAEs) occurring in at least 10% of patients were nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%). Importantly, the majority of these Revolution Medicines adverse events were classified as Grade 1 or 2 in severity. Only a small subset of patients (2%) experienced Grade 3 TRAEs, which were reversible upon dose interruption. TheseRevolution Medicines data suggest that zoldonrasib is generally well tolerated by patients, with a favorable mean dose intensity of 98%. No dose-limiting toxicities (DLTs) were observed during the study, further reinforcing the compound’s safety profile.
In addition, the study monitored the potential for more severe adverse effects, but none were found to significantly impact patients’ ability to continue treatment. The results were consistent with the safety data previously observed in other indications, such as pancreatic cancer, indicating that zoldonrasib’s side effect profile is manageable and generally not a limiting factor in its administration.
Encouraging Antitumor Activity in KRAS G12D Mutant Non-Small Cell Lung Cancer
Preliminary antitumor activity was assessed in a cohort of 18 efficacy-evaluable patients with NSCLC, all of whom harbored the KRAS G12D mutation. This group of patients received the recommended Phase 2 dose of 1200 mg of zoldonrasib Revolution Medicines once daily. Notably, the objective response rate (ORR) in this small cohort was 61%, with 11 patients demonstrating confirmed or pending confirmation of a response. Additionally, the disease control rate (DCR) in this group was 89%, with 16 patients experiencing stable disease or better.
These early efficacy data are particularly promising given the high unmet need in the treatment of KRAS G12D mutant NSCLC. To date, no targeted therapies have been approved for cancers harboring this specific mutation, which makes zoldonrasib’s potential as a treatment option especially important. The results of this trial suggest that zoldonrasib may fill a significant gap in the available therapeutic options for these patients, providing a new potential avenue for treatment.
Dr. Kathryn Arbour, M.D., a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, served as the principal investigator and lead author for the RMC-9805-001 study presentation. Dr. Arbour commented, “There is an urgent need for novel treatments within the KRAS G12D mutant cancer patient population, as current treatment options are limited and often ineffective. While these data are from an early, small subset of patients, it is encouraging to observe this level of tolerability and promising antitumor activity in patients with NSCLC carrying the KRAS G12D mutation. This study underscores the potential of zoldonrasib as an innovative therapy for this challenging patient group.”
Implications for Future Research and Development
These initial results support the continued development of zoldonrasib as a targeted therapeutic for patients with KRAS G12D mutant cancers, particularly in NSCLC, where treatment options are scarce. The favorable safety and promising Revolution Medicines efficacy profile observed in this Phase 1 study lay the foundation for further investigation of zoldonrasib in larger, more diverse patient populations. Moreover, the data suggest that zoldonrasib could potentially be evaluated in combination with other therapies to enhance its antitumor effects.
Revolution Medicines intends to expand the clinical evaluation of zoldonrasib, both as a monotherapy and in combination with other agents, in future clinical trials. This will include evaluating its potential in other tumor types that harbor the KRAS G12D mutation, such as pancreatic cancer, colorectal cancer, and other solid tumors. Additionally, Revolution Medicines the company is exploring the possibility of combining zoldonrasib with immune checkpoint inhibitors and other targeted therapies to assess potential synergies in treating cancers with RAS mutations.
“As we continue to advance zoldonrasib through the clinical development pipeline, we are encouraged by these early results and the potential impact of this drug for patients with KRAS G12D-mutant cancers,” said Dr. Goldsmith. “Our team remains committed to exploring all avenues to bring this promising treatment to the patients who need it most, and we look forward to sharing additional updates as we move forward with these important trials.”
About Zoldonrasib and Revolution Medicines
Zoldonrasib is an oral, selective inhibitor of the RAS(ON) G12D mutation, designed to target and inhibit the activity of the KRAS G12D mutant protein, which is involved in driving the growth and survival of various cancers. Revolution Medicines is a clinical-stage biopharmaceutical company focused on developing targeted therapies to treat cancers driven by RAS mutations, which are among the most common and challenging targets in oncology.
By focusing on RAS-addicted cancers, including NSCLC, pancreatic cancer, and colorectal cancer, Revolution Medicines aims to address the significant unmet needs of patients whose cancers are driven by these mutations. The Revolution Medicines company is advancing multiple investigational therapies in clinical trials, with the goal of providing new, effective treatment options for patients with RAS-driven cancers.
