The oral KRAS G12D inhibitor zoldonrasib could provide clinical benefit in patients with previously treated non–small cell lung cancer (NSCLC) whose tumors harbored a KRAS G12D mutation, according to new findings presented by Arbour et al at the 2025 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT019).
Background
The KRAS gene is one of the most frequently mutated genes among human cancer types, with a variety of mutations found at different rates in different tumor types. Two inhibitors targeting the KRAS G12C mutation—which accounts for about 13% of NSCLC-related mutations—have been approved by the U.S. Food and Drug Administration for treatment in patients with KRAS G12C–mutated NSCLC.
However, approximately 4% of NSCLC cases harbor KRAS G12D mutations, which currently have no approved targeted therapies. The standard of care among patients with previously treated, KRAS G12D–mutated NSCLC is typically docetaxel, which has an objective response rate of 10% to 15%.
“While patients with KRAS G12D–mutated NSCLC are most commonly treated with chemotherapy and immune checkpoint inhibitors, they often do not benefit substantially from these therapies, and prognosis is poor,” stressed lead study author Kathryn C. Arbour, MD, an assistant attending and thoracic medical oncologist at Memorial Sloan Kettering Cancer Center. “Therefore, developing novel therapies for this patient population is of paramount importance,” she added.
Zoldonrasib is a novel RAS(ON) tricomplex inhibitor that selectively targets the KRAS G12D mutation. Unlike currently approved KRAS G12C–targeted therapies, which lock mutated KRAS in an inactive conformation, zoldonrasib is designed to target the active conformation of KRAS. This may delay or prevent treatment resistance because the cell cannot circumvent the blockade by boosting upstream signaling, maintaining KRAS in its active conformation.
Study Methods and Results
In the phase I clinical trial, researchers analyzed the safety and efficacy of zoldonrasib in 211 patients with KRAS G12D–mutated solid tumors who had received at least one prior line of therapy. They noted that 90 of the patients were treated at the recommended phase II dose of 1,200 mg per day. The maximum tolerated dose was not reached.
The researchers reported no grade 4 or 5 treatment-related adverse effects. However, among the patients who received 1,200-mg doses, one patient discontinued treatment, four patients reduced their doses, and eight patients had dose interruptions as a result of treatment-related adverse effects. Although toxicities such as rashes, mucositis, and transaminitis have been observed with other RAS-targeted therapies, these adverse effects were not observed during treatment with zoldonrasib.
“Zoldonrasib was very well tolerated at all dose levels, including the 1,200 mg once-daily dose. The most common [adverse] effects were nausea, diarrhea, and fatigue, typically low-grade and easily managed with supportive medications,” Dr. Arbour detailed.
In the efficacy analysis, the researchers included 18 patients with NSCLC who enrolled at least 8 weeks prior to the data cutoff. Among these patients, 61% of them experienced an objective response, and 89% of them experienced disease control.
Conclusions
“Patients with tumors harboring [the KRAS G12D] mutation are in need of new treatment options,” Dr. Arbour emphasized. “The ability to target KRAS G12D in a selective manner with an oral therapy that is well tolerated will hopefully change the treatment landscape for patients with this subtype of NSCLC,” she highlighted.
Study limitations included its small sample size and short follow-up duration. Future studies involving larger cohorts and longer follow-ups will be critical to assess the potential clinical impact of zoldonrasib.
“These data represent a substantial advance for patients with KRAS G12D–mutated [NSCLC],” Dr. Arbour underscored. “We’ve shown for the first time that selectively targeting KRAS G12D is feasible and well tolerated in this distinct population of patients with NSCLC,” she concluded.
Disclosure: The research in this study was funded by Revolution Medicines. For full disclosures of the study authors, visit aacrjournals.org.
