Zoldonrasib Shows Encouraging Early Antitumor Activity in KRAS G12D–Mutated NSCLC

Zoldonrasib in KRAS G12D–Mutated

NSCLC | Image Credit: © Kellie Ehrmann/

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Zoldonrasib (RMC-9805) demonstrated preliminary antitumor activity with favorable tolerability and a manageable toxicity profile in patients with non–small cell lung cancer (NSCLC) harboring KRAS G12D mutations, according to findings from arm A of the phase 1 RMC-9805-001 study (NCT06040541) presented in a press briefing during the 2025 AACR Annual Meeting.1

At a data cutoff date of December 2, 2024, an objective response rate (ORR) of 61% was reported in evaluable patients with NSCLC who received the agent at 1200 mg once daily (QD; n = 18); the disease control rate (DCR) was 89%. Moreover, the median time to response was 1.4 months (range, 1.2-2.8) and the median time on treatment was 2.6 months (range, 1.3-8.0).

Safety was evaluated in 90 patients who received zoldonrasib at 1200 mg once daily, and treatment-related adverse effects (TRAEs) were noted to be mostly grade 1 (54%); 18% of patients experienced grade 2 events and 2% experienced grade 3 events. Notably, no grade 4 or 5 TRAEs or serious AEs were observed. As such, 1200 mg once daily has been identified as the recommended phase 2 dose.

“Dose optimization and expansion are currently ongoing in patients with lung cancer and other solid tumor types,” Kathryn C. Arbour, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, said in the briefing. “Preliminary safety and antitumor activity of zoldonrasib can support the continued development of this agent as monotherapy, and it is also being explored in combination with other therapies.”

Inspiration Behind the Research

Nearly 61,000 cases of cancer harboring a RAS G12D mutation will be diagnosed in the United States annually; this represents approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases, 15% of colorectal cancer cases, and 4% of NSCLC cases, according to Arbour. “And yet, there are currently no approved targeted therapies for RAS G12D,” she said. Within NSCLC, KRAS G12D mutations are commonly linked with never smoker status, lower expression of PD-L1, and lower tumor mutational burden (TMB) vs other non-G12D subtypes. KRAS G12D mutations have also been associated with suboptimal efficacy achieved with immune checkpoint inhibition, she added.

Zoldonrasib represents a therapeutic approach that has been designed to target RAS G12D in the GTP-bound or ON state. The mutant-selective covalent inhibitor of RAS(ON) G12D proteins has demonstrated early activity in patients with PDAC, with an ORR of 30% and a DCR of 80%, when given at a dose of 1200 mg QD.2

A Closer Look at the Trial Design

The phase 1 RMC-9805-001 study included patients with advanced solid tumors harboring KRAS G12D mutations who had previously received standard treatment appropriate for their tumor and disease stage, had an ECOG performance status of 0 or 1, and did not have any active brain metastases.

The study is comprised of two parts. In the first part, or the dose-escalation portion, patients were administered zoldonrasib orally QD or twice daily (BID) as part of 21-day treatment cycles. The doses explored included 150 mg QD, 300 mg QD, 600 mg QD, 900 mg QD, and 1200 mg QD, as well as 300 mg BID, 450 mg BID, and 600 mg BID.

“During dose escalation, no dose-limiting toxicities were reported at any dose or schedule, and the maximum tolerated dose of zoldonrasib was not reached,” Arbour said. Part 2 continued dose expansion and optimization in two tumor types of interest: NSCLC and pancreas cancer.

The key end points of the study include safety and tolerability, pharmacokinetics, and antitumor activity.

Understanding the Patient Population

At the time of date cutoff, a total of 211 patients spanning tumor types had received zoldonrasib at any dose. The median patient age was 62 years (range, 25-86), 55% were male, and 70% had an ECOG performance status of 1. Regarding tumor type, 14% of patients had NSCLC, 55% had PDAC, and the remaining 31% had other. The number of prior anticancer therapies received was 2 (range, 0-10). Sixty-nine percent of patients had baseline liver metastases and 61% had metastatic disease at the time of diagnosis.

“The baseline characteristics of those patients treated at the 1200-mg dose were consistent with the overall population,” Arbour said. At the time of data cutoff, 28 patients with KRAS G12D–mutant NSCLC had received zoldonrasib at 1200 mg QD. The median patient age was 64 years (range, 36-86), 50% were male, and 64% had an ECOG performance status of 1. Moreover, 54% were never smokers, 43% were past smokers, and 4% were current smokers. The number of previous anticancer therapies received was again 2 (range, 0-6), with 86% of patients having previously received platinum chemotherapy and 86% having received immune checkpoint inhibition. Twenty-one percent of patients had baseline brain metastases and 75% had metastatic disease at diagnosis.

Case Study Spotlight

Arbor also shared a case study of a 36-year-old Asian woman who was a never smoker and had no previous medical history. This patient had an initial diagnosis KRAS G12D–mutant NSCLC with stage IIIA disease and low TMB and a PD-L1 expression below 1%. Extensive lymphangitic carcinomatosis involvement was observed on baseline scans, she underscored. For her stage IIIA disease, she was given neoadjuvant chemoimmunotherapy with carboplatin, pemetrexed, and nivolumab (Opdivo) followed by surgical resection, Arbour said. While receiving adjuvant atezolizumab (Tecentriq), she experienced metastatic recurrence and subsequently received left lung radiotherapy followed by chemoimmunotherapy with carboplatin, paclitaxel, atezolizumab, and the addition of bevacizumab (Avastin).

This patient was administered 1200 mg QD of zoldonrasib and experienced a partial response by RECIST 1.1 criteria at the first follow-up scan at cycle 3 day 1, and her response proved to deepen over time. Regarding safety, she experienced a TRAE of grade 1 nausea which resolved in 9 days. She also had a grade 3 increase in creatinine phosphokinase, which was suspected to be linked with an increase in exercise as she returned to the gym, Arbour explained. Her dose was interrupted and resumed at 900 mg QD. Within 1 week of cycle 1 day 1, her cough resolved, and she came off oxygen.

Safety Insights

The most common TRAEs experienced with zoldonrasib that were reported in at least 10% of patients included nausea (grade 1, 33%; grade 2, 6%; grade 3, 0%), diarrhea (20%; 3%; 1%), vomiting (13%; 4%; 0%), and rash (12%; 0%; 0%). Other select TRAEs included increased aspartate aminotransferase (grade 1, 6%; grade 2, 2%; grade 3, 0%), increased alanine aminotransferase (4%; 1%; 1%), and stomatitis or mucositis (1%; 0%; 0%).

TRAEs led to dose reduction for 4% of patients (n = 90) and dose interruption for 9% of patients. Only 1 patient experienced a TRAE that led to treatment discontinuation; this patient experienced grade 1 pneumonitis. The mean dose intensity at 1200 mg QD was 98%.

What’s Next?

Zoldonrasib is being explored in combination with daraxonrasib (RMC-6236) in patients with solid tumors as part of this study, with standard-of-care (SOC) regimens in patients with NSCLC as part of a phase 1/2 study (NCT06162221), and with SOC regimens in patients with gastrointestinal cancers as part of a phase 1/2 study (NCT06445062).

Disclosures: Dr Arbour serves on the advisory board for Bristol Myers Squibb, Revolution Medicines, Merck, Amgen, Regeneron, AstraZeneca, G1 Therapeutics, and Novartis. She disclosed grant/research support was provided by Revolution Medicines, Bristol Myers Squibb, Mirati, Genentech, and Lilly.

References

1. Arbour KC, Tawee T, Yaeger R, et al. CT019 - Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT019.
2. Spira A, Papadopoulos K, Kim D, et al. Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors. J Clin Oncol. 2025;43(4):724. doi:10.1200/JCO.2025.43.4_suppl.724