Early ctDNA Clearance Is Associated With Response to Daraxonrasib in RAS-Mutant NSCLC

RAS-Mutated NSCLC |
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The early clearance of circulating tumor DNA (ctDNA) was associated with clinical responses in patients with advanced non–small cell lung cancer (NSCLC) harboring RAS G12X mutations treated with daraxonrasib (RMC-6236), according to data from an analysis of a phase 1 trial (NCT05379985).1

Findings presented at the 2025 AACR Annual Meeting showed that among ctDNA-evaluable patients (n = 35), 66% experienced complete ctDNA clearance, defined as a 100% reduction in RAS variant allele frequency (VAF). Among 11 ctDNA-evaluable patients who achieved a partial response (PR) on the study, 82% experienced complete ctDNA clearance. In patients who had a best response of stable disease (SD; n = 21) and progressive disease (PD; n = 3), the rates of patients with complete ctDNA clearance were 67% and 0%, respectively.

“Additionally, ctDNA clearance was seen across all RAS G12X mutations, [including] KRAS G12D, KRAS G12V, KRAS G12A, [and] KRAS G12S [mutations], and across a wide range of VAFs in baseline ctDNA,” lead study author Jia Luo, MD, and colleagues wrote in a poster presentation of the data.

Luo is a physician at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School in Boston, Massachusetts.

Efficacy Data for Daraxonrasib

Efficacy findings from the phase 1 study, which were also presented at the 2025 European Lung Cancer Congress, showed that patients with RAS G12X–mutant NSCLC (n = 40) who received daraxonrasib in the second- or third-line setting at a dose ranging from 120 mg to 220 mg once per day achieved a confirmed overall response rate (ORR) of 38%, which was comprised exclusively of PRs.1,2 The median duration of response (DOR) was 15.1 months (95% CI, 11.1-not evaluable [NE]), and the median time to response was 1.5 months (range, 1.2-6.2).

The median progression-free survival (PFS) and median overall survival (OS) were 9.8 months (95% CI, 6.0-12.3) and 17.7 months (95% CI, 13.7-NE).1

Daraxonrasib and Phase 1 Trial Background

Daraxonrasib is a multi-selective, tri-complex RAS(ON) inhibitor intended to prevent RAS(ON) signaling in RAS-mutated solid tumors, such as NSCLC.

The phase 1 trial evaluated the agent in patients with solid tumors—including NSCLC—harboring RAS mutations, including KRAS, HRAS, and NRAS at codons 12, 13, or 61. Notably, patients with KRAS G12C–mutated NSCLC were not permitted to enroll.

During dose escalation, patients received daraxonrasib once per day at doses of 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 220 mg, 300 mg, or 400 mg. Doses ranging from 160 mg to 300 mg were explored for optimization in patients with NSCLC.

The end points of the study were safety/tolerability, antitumor activity, and pharmacokinetics/pharmacodynamics.

For the ctDNA analysis, testing was performed on paired plasma samples at day 1 of cycles 1 and 2 or cycles 1 and 3.

Baseline Characteristics and ctDNA Analysis

The median age of all patients with NSCLC treated with daraxonrasib at 160 mg per day or 220 mg per day (n = 73) was 68 years (range, 36-89). Thirty-eight percent of patients were male, 81% had an ECOG performance status of 1, 73% were past or current smokers, 26% had brain metastases at baseline, and 51% had stage IV disease at diagnosis.

Of the 56 patients who underwent ctDNA testing, 49 had samples collected at day 1 of cycles 1 and 2, and the remainder had samples taken at day 1 of cycles 1 and 3. Sixty-three percent of patients in this population (n = 35/56) had a RAS G12X mutation detected in ctDNA at baseline. PRs or SD were also observed across VAFs, ranging from 0.04% to 52.05%.

Safety Data

No grade 4 or 5 treatment-related adverse effects (TRAEs) were reported. TRAEs led to dose interruption in 34% of patients, dose reduction in 21% of patients, and treatment discontinuation in 4% of patients. The mean dose intensity was 91%.

Any-grade TRAEs and grade 3 TRAEs occurred at rates of 97% and 16%, respectively, The most common TRAEs included rash (any-grade, 90%; grade 3, 7%), diarrhea (63%; 1%), nausea (49%; 0%), vomiting (40%; 3%), stomatitis (34%; 0%), paronychia (19%; 0%), increased aspartate aminotransferase levels (15%; 0%), increased alanine aminotransferase levels (14%; 0%), dry skin (12%; 0%), and fatigue (11%; 0%). Anemia as a TRAE was reported at any grade in 6% of patients and at grade 3 in 3% of patients.

References

1. Luo J, Punekar SR, Arbour KC, et al. Early reduction in circulating tumor DNA (ctDNA) is associated with clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC). Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract LB218.
2. Punekar S, Hong DS, Luo J, et al. Safety and clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2025;20(3):S10-S11. doi:10.1016/S1556-0864(25)00201-1