Zoldonrasib Shows ‘Encouraging’ Activity in Patients With NSCLC Harboring KRAS G12D Mutation

Zoldonrasib showed “encouraging initial antitumor activity” in patients with non–small cell lung cancer (NSCLC) who are harboring the KRAS G12D mutation, according to a study presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting.

Kathryn C. Arbour, MD, an assistant attending and thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, presented the study at the AACR Annual Meeting. Dr. Arbour explained in an AACR press release why it was critical to investigate the novel therapy for patients harboring the KRAS G12D mutation, which has no approved targeted therapies.

“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,” Dr. Arbour said in a statement provided by the AACR. “Therefore, developing novel therapies for this patient population is of paramount importance.”

Zoldonrasib is a novel RAS(ON) tri-complex inhibitor that selectively targets the KRAS G12D alteration and has unique features.

“Unlike currently approved KRAS G12C-targeted therapies, which lock mutated KRAS in an inactive conformation, zoldonrasib targets the active conformation of KRAS,” officials explained a news release about the study. “This may delay or prevent resistance because the cell cannot circumvent the blockade by boosting upstream signaling, maintaining KRAS in its active conformation.”

The phase 1 study included patients with previously treated advanced KRAS G12D solid tumors, with 211 patients receiving five escalating dose levels of zoldonrasib monotherapy as of the December 2, 2024, data cutoff. Patients received escalating doses of zoldonrasib 150 to 1,200 mg once daily or 300 to 600 mg twice daily. The study investigators assessed antitumor activity every 6 weeks for the first 24 weeks and then every 9 weeks. The study enrolled additional patients at doses that “cleared the dose-limiting toxicity (DLT) evaluation to further characterize pharmacokinetics, safety, and antitumor activity of zoldonrasib,” the researchers explained.

The study showed that the maximum tolerated dose of zoldonrasib has not been reached, and the investigators reported no DLTs or grade 4 or 5 treatment-related adverse events (TRAEs).

Among the 90 patients who received a candidate-recommended phase 2 dose of 1,200 mg once a day, the most common TRAEs, occurring in at least 10% of patients, were:

• Nausea (39%)
• Diarrhea (24%)
• Vomiting (18%)
• Rash (12%)

The TRAEs were “primarily Grade 1 or 2 in severity with the exception of 1 patient with Grade 3 diarrhea and 1 patient with Grade 3 ALT elevation,” but the researchers noted that both of the grade 3 TRAEs “resolved following dose interruption.” Among the 90 patients who received the 1,200-mg dose, one patient discontinued treatment, four patients had dose reductions, and eight patients had dose reductions due to a TRAE.

Dr. Arbour explained that side effects and toxicities such as rash, mucositis, and transaminitis that have been observed with other RAS-targeted therapies have not been reported with zoldonrasib.

“Zoldonrasib was very well tolerated at all dose levels, including the 1,200 mg once-daily dose. The most  common side effects were nausea, diarrhea, and fatigue, typically low-grade and easily managed with supportive medications,” Arbour said in a statement provided by the AACR.

In addition to the safety data, the study also showed that at daily doses of at least 600 mg, “exposures to zoldonrasib were within the range of preclinical exposures that induced tumor regressions in mice,” according to the abstract. In the 18 patients with NSCLC receiving 1,200 mg daily who enrolled at least 8 weeks prior to the data cutoff, the objective response rate was 61% (95% CI, 36%-83%), with a median of 1.4 months to onset of initial response (range, 1.2-2.8 months). The disease control rate was 89% (95% CI, 65%-99%).

Dr. Arbour explained in the AACR press release that the standard of care for patients with previously treated, KRAS G12D-mutated NSCLC is “typically the chemotherapy docetaxel, which has an objective response rate of around 10% to 15%.”

“Patients with tumors harboring this mutation are in need of new treatment options,” Dr. Arbour said in a statement provided by the AACR. “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.”

In addition, Dr. Arbour emphasized the importance of further study in larger populations and with longer follow-up duration, while noting that she is encouraged by these initial results of the phase 1 study.

At top, study author Kathryn C. Arbour, MD, an assistant attending and thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, is shown. (Photo courtesy of the AACR).

Sources:

American Association for Cancer Research. Accessed April 24, 2024. https://www.aacr.org/about-the-aacr/newsroom/news-releases/oral-investigational-agent-zoldonrasib-elicits-objective-responses-in-patients-with-kras-g12d-mutated-lung-cancer/

2025 American Association for Cancer Research Annual Meeting. Abstract #CT019. https://www.abstractsonline.com/pp8/#!/20273/presentation/10422