AACR 2025: Oral Investigational Agent Zoldonrasib Elicits Objective Responses in Patients With KRAS G12D-Mutated NSCLC

Promising early-phase clinical trial results were presented for zoldonrasib (RMC-9805; Revolution Medicines), a novel oral therapeutic agent targeting the KRAS G12D mutation in patients with non–small cell lung cancer (NSCLC) at the American Association for Cancer Research (AACR) Annual Meeting 2025 in Chicago, Illinois. These preliminary findings suggest that zoldonrasib, a first-in-class RAS(ON) G12D-selective tri-complex inhibitor, may offer a new avenue of treatment for a subset of lung cancer patients who currently have limited targeted therapy options.

Microscopic view of non small cell lung cancer cells. Image Credit: © Keopaserth - stock.adobe.com

KRAS is one of the most commonly mutated oncogenes, with different variants contributing to various tumor types. In NSCLC, mutations in KRAS are present in approximately 25% to 30% of patients, with the G12C mutation being the most prevalent. FDA-approved therapies such as sotorasib (Lumakras; Amgen) and adagrasib (Krazati; Bristol Myers Squibb) target KRAS G12C and have provided clinical benefit for patients harboring this mutation. However, approximately 4% of patients with NSCLC carry the KRAS G12D mutation, for which no approved targeted therapy exists. This absence underscores a significant unmet need in lung cancer treatment, particularly for patients who have already undergone standard therapies such as chemotherapy and immunotherapy without significant or lasting response to therapy.

Kathryn C. Arbour, MD, an assistant attending and thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, presented the data at the AACR Annual Meeting from the phase 1 trial (NCT06040541) evaluating zoldonrasib in patients with advanced solid tumors harboring the KRAS G12D mutation. According to Arbour, patients with KRAS G12D-mutated NSCLC are often treated with chemotherapy or immune checkpoint inhibitors (ICIs), yet they frequently derive limited benefit.

“While patients with KRAS G12D–mutated NSCLC are most commonly treated with chemotherapy and ICIs, they often do not benefit substantially from these therapies, and prognosis is poor,” Arbour said in an AACR statement. “Therefore, developing novel therapies for this patient population is of paramount importance.”

Zoldonrasib distinguishes itself mechanistically from other KRAS-targeted therapies, according to the study investigators. While KRAS G12C inhibitors function by locking the mutated protein in an inactive state, zoldonrasib targets the active, guanosine triphosphate–bound conformation of KRAS G12D. This unique approach may help delay or circumvent resistance, a common issue with targeted therapies, by maintaining effective inhibition even when upstream signaling is active. Zoldonrasib acts by forming a covalent tri-complex with the mutated RAS protein, a strategy that enhances selectivity and potency.

The phase 1 study enrolled a total of 211 patients with KRAS G12D-mutated advanced solid tumors. These patients had received at least 1 prior line of treatment, and the study tested escalating doses of zoldonrasib ranging from 150 mg to 1200 mg administered once daily or 300 to 600 mg twice daily. A significant cohort of 90 patients was treated at the 1200-mg daily dose, which emerged as the recommended phase 2 dose (RP2D). Notably, the maximum tolerated dose was not reached, and no dose-limiting toxicities or grade 4/5 treatment-related adverse events (TRAEs) were observed.

From a safety perspective, zoldonrasib was well tolerated across all tested dose levels. The most common AEs were gastrointestinal in nature—nausea (39%), diarrhea (24%), vomiting (18%)—as well as rash (12%). Most AEs were grade 1 or 2 in severity, and only 2 patients experienced grade 3 toxicities: 1 with diarrhea and another with elevated alanine transaminase. Both of these AEs resolved after dose interruption. Of the patients receiving the 1200-mg dose, only 1% discontinued treatment due to TRAEs, while dose reductions and interruptions were relatively rare (4% and 9%, respectively).

Importantly, zoldonrasib also demonstrated early signals of clinical efficacy. The efficacy analysis focused on 18 patients with NSCLC who had received the RP2D and had enrolled at least 8 weeks prior to the data cutoff on December 2, 2024. Among these patients, the confirmed or pending-confirmation objective response rate (ORR) was 61%, with a disease control rate (DCR) of 89%. The median time to initial response was 1.4 months, indicating that the drug began to exert effects relatively quickly.

This represents a substantial improvement compared with the historical ORR for docetaxel, the standard treatment for previously treated NSCLC, which typically yields response rates between 10% and 15%. These early results thus suggest that zoldonrasib could significantly alter the treatment landscape for patients with KRAS G12D-mutated NSCLC.

Arbour emphasized that while the trial is still in its early stages, the data present a meaningful advance. “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,” Arbour said. She also pointed out that toxicities often associated with RAS-targeted agents—such as rash, mucositis, and transaminitis—were not seen with zoldonrasib, which may be attributed to its novel mechanism of action.

However, there are limitations to the current data. The relatively small number of NSCLC patients evaluated for efficacy (n = 18) and the short duration of follow-up mean that long-term outcomes, such as progression-free survival and overall survival, remain unknown. Larger studies with extended observation periods will be needed to confirm the durability of responses and better characterize the therapeutic potential of zoldonrasib.

Encouraged by the phase 1 findings, further development of zoldonrasib is already underway. Ongoing studies are evaluating the drug not only as a monotherapy but also in combination with other treatment modalities, including immunotherapies, chemotherapies, and other targeted agents. A follow-up clinical trial (NCT06162221) is being planned to further assess these combinations and optimize therapeutic strategies for patients with KRAS G12D-mutant NSCLC.

REFERENCE

Single-cell RNA sequencing provides comprehensive map of acute myeloid leukemia cell states. News release. AACR. April 27, 2025. Accessed April 18, 2025. https://aacr.ent.box.com/s/6yarrl35ziyqz1jveylbncghegkca59p