Daraxonrasib Generates Clinical Activity With Manageable Safety in RAS-Mutant NSCLC

Daraxonrasib in RAS-Mutant NSCLC
| Image Credit: © Sebastian Kaulitzki

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The multi-selective, tricomplex RAS(ON) inhibitor daraxonrasib (RMC-6236) yielded clinical activity and displayed a manageable safety profile in patients with previously treated non–small cell lung cancer (NSCLC) harboring RAS mutations, according to data from the first-in-human phase 1 RMC-6236-001 trial (NCT05379985).1

Findings presented at the 2025 European Lung Cancer Congress demonstrated that patients with NSCLC harboring RAS G12X mutations treated with daraxonrasib in the second- or third-line setting at a dose of 120 mg to 220 mg per day (n = 40) experienced an overall response rate (ORR) of 38%, which was comprised exclusively of partial responses. The median time to response was 1.5 months (range, 1.2-6.2), and the median duration of response (DOR) was 15.1 months (95% CI, 11.1-not evaluable [NE]).

Regarding safety, treatment-related adverse effects (TRAEs) led to dose interruptions, dose reductions, and treatment discontinuation in 48%, 27%, and 6% of patients treated with daraxonrasib at a dose of 120 mg to 300 mg per day (n = 124), respectively; a total of 52% of these patients required any dose modifications due to TRAEs. Additionally, 41% of patients treated at doses ranging from 120 mg to 220 mg per day (n = 73) required dose modifications due to TRAEs; the respective rates of dose interruption, dose reduction, and treatment discontinuation were 34%, 21%, and 4%.

Among patients treated at 120 mg to 220 mg, grade 3 or higher treatment-related rash occurred in 9% of patients who did not receive prophylaxis (n = 58), and 7% of these patients required dose modifications due to treatment-related rash. In patients who did receive rash prophylaxis, none experienced grade 3 or higher rash or required dose modifications due to treatment-related rash.

The 200-mg dose was selected for further evaluation in phase 3 testing.

“Based on these data, a randomized phase 3 study called RASolve 301 [NCT06881784] of daraxonrasib vs docetaxel in patients with previously treated, locally advanced or metastatic RAS-mutant NSCLC has been initiated,” lead study author Salman R. Punekar, MD, said in a presentation of the data. Punekar is an assistant professor in the Department of Medicine at New York University (NYU) Grossman School of Medicine of NYU Langone Health.

RMC-6236-001 Overview

The first-in-human study evaluated daraxonrasib in patients with histologically confirmed advanced solid tumors RAS mutations.2 During dose-escalation, KRAS G12D mutations were required; RAS mutations confirmed via DNA sequencing were needed for dose optimization/expansion. Prior standard therapy appropriate for a patient’s tumor type and stage was required. Other key inclusion criteria consisted of an ECOG performance status of 0 or 1 and adequate organ function.

The study included patients with KRAS, HRAS, or NRAS mutations at codon 12, codon 13, or codon 61; patients with KRAS G12C mutations were enrolled in the NSCLC cohort.1

During dose escalation, daraxonrasib was evaluated at once-daily doses ranging from 10 mg to 400 mg. The 120-, 160-, 220-, and 300-mg doses were selected for the dose-optimization phase.

Safety and the incidence of dose-limiting toxicities are the trial’s primary end points.2 Secondary end points include pharmacokinetics, ORR, DOR, TTR, disease control rate, and progression-free survival (PFS).

In all patients with NSCLC treated with daraxonrasib at 120 mg to 300 mg per day (n = 124), the median age was 67 years (range, 31-89), and 60% were female.1 Eighty-one percent of patients had an ECOG performance status of 1, and 76% of patients were current or past smokers. Fifty-seven percent of patients had metastatic disease at diagnosis, and 29% had baseline brain metastases. Patients received a median of 2 prior lines of therapy (range, 1-6).

Additional Efficacy and Safety Data

Findings also demonstrated that patients treated with daraxonrasib at 120 mg to 220 mg per day achieved a median PFS of 9.8 months (95% CI, 6.0-12.3) and a median overall survival of 17.7 months (95% CI, 13.7-NE).

The most common TRAEs reported in at least 10% of patients treated with daraxonrasib at 120 mg to 300 mg per day included rash (any-grade, 89%; grade ≥3, 7%), diarrhea (70%; 8%), nausea (55%; 0%), vomiting (44%; 2%), stomatitis (38%; 2%), paronychia (21%; 0%), fatigue (16%; 0%), dry skin (15%; 0%), increased aspartate aminotransferase levels (14%; 1.6%), increased alanine aminotransferase levels (12%; 2.4%), decreased appetite (11%; 0%), and dysgeusia (10%; 0%).

Disclosures: Punekar did not report any conflicts of interest.

References

1. 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
2. Study of RMC-6236 in patients with advanced solid tumors harboring specific mutations in RAS. ClinicalTrials.gov. Updated November 14, 2024. Accessed April 7, 2025. https://clinicaltrials.gov/study/NCT05379985