AACR 2025 | Zoldonrasib demonstrates promising clinical benefit for KRAS G12D-mutated NSCLC
Objective responses observed with oral, investigational drug zoldonrasib for KRAS G12D-mutated NSCLC patients.
Findings from a Phase I trial presented at the AACR Annual Meeting (25–30 April; Chicago, IL, USA) have highlighted encouraging efficacy reports of using zoldonrasib in NSCLC patients with KRAS G12D mutations. Current US FDA approved therapies target KRAS G12C, which makes up around 13% of NSCLC mutations, however, KRAS G12D mutations contribute to approximately 4% of these cancer cases with no approved therapies yet to target it.
Study presenter, Kathryn C. Arbour (Memorial Sloan Kettering Cancer Centre, NY, USA) stated: “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” highlighting the need for an effective treatment options for patients diagnosed with this NSCLC subtype.
Zoldonrasib, a RAS(ON) tri-complex inhibitor, utilizes a mechanism of action of selective binding to the active form of KRAS. The targeting of the active form includes benefits such as preventing resistance due to upstream signaling changes. In contrast, existing therapies work by locking KRAS in an inactive conformation.
The Phase I clinical trials recruited 211 patients with KRAS G12D-mutated solid tumors who had undergone a minimum of one prior therapy. Overall, 90 patients were administered Phase II dose of 1,200 mg daily. Arbour explained the trends in observed side effects: “Zoldonrasib was very well tolerated at all dose levels… The most common side effects were nausea, diarrhea, and fatigue, typically low-grade and easily managed.”
Compared to docetaxel, which typically provides a 10–15% response rate, efficacy analysis of 18 NSCLC patients treated with zoldonrasib highlighted that 89% experienced disease control and 61% has an objective response.
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“These data represent a substantial advance for patients with KRAS G12D-mutated lung cancer. 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,” commented Arbour.
Whilst the trial yielded positive outcomes, it was limited by a small sample size and short follow up period. To validate the results discussed, further studies need to be conducted with larger patient groups and longer follow-ups.