Daraxonrasib Yields Durable Responses in Previously Treated RAS-Mutant NSCLC

Daraxonrasib (Rasonque), an oral RAS(ON) multiselective tri-complex inhibitor of GTP-bound mutant and wild-type RAS protein isoforms, produced durable objective responses in patients with previously treated, advanced RAS-mutant non–small cell lung cancer (NSCLC) whose disease had progressed on platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy, according to data from the phase 1/2 RMC-6236-001 trial (NCT05379985) published in The New England Journal of Medicine.¹

Among patients who had received previous first- or second-line platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy but not docetaxel and who were treated with daraxonrasib at doses of 160 mg to 220 mg (n = 38), a confirmed complete or partial response was observed in 42% (95% CI, 26%-59%) of those with any RAS mutation, with a median duration of response (DOR) of 11.5 months (95% CI, 4.6-not estimable [NE]) and a median time to response of 1.4 months (range, 1.2-6.2). In this population, the median progression-free survival (PFS) was 8.3 months (95% CI, 4.0-12.5), and the median overall survival (OS) was 16.0 months (95% CI, 9.5-NE).

Response rates were consistent across dose levels in the full safety and efficacy population (n = 136). A confirmed response was observed in 31% (95% CI, 14%-52%) of patients who received daraxonrasib at 120 mg or less (n = 26), 34% (95% CI, 22%-47%) of those who received the agent at 160 mg to 220 mg (n = 59), and 37% (95% CI, 24%-52%) of those who received the agent at 300 mg (n = 51). Among the 33 patients with RAS G12–mutant NSCLC who received daraxonrasib at 160 mg to 220 mg, a confirmed response was observed in 42% (95% CI, 25%-61%), the median DOR was not estimable (95% CI, 4.6 months-NE), and the Kaplan-Meier estimated percentage of patients with an ongoing response at 18 months was 51% (95% CI, 21%-75%).

“Among patients with RAS-mutant NSCLC who had disease progression after platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy, daraxonrasib was associated with adverse effects [AEs] of grade 3 or higher, regardless of attribution, in 54% and treatment-related AEs [TRAEs] of grade 3 or higher in 30%, along with a response in more than 30% of patients,” the study authors, led by Kathryn C. Arbour, MD, wrote.

Arbour is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

How was the RMC-6236-001 trial designed?

The RMC-6236-001 trial is a multicenter, open-label, 2-part dose-escalation and dose-expansion study of daraxonrasib in patients with advanced solid tumors harboring RAS mutations; this analysis focused on the NSCLC subgroup. Eligible patients were 18 years or older with histologically confirmed, previously treated advanced NSCLC harboring nonsynonymous mutations in KRAS, NRAS, or HRAS at codons 12, 13, or 61 (G12, G13, or Q61), an ECOG performance status of 0 or 1, and disease progression during platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy or unacceptable toxicity with these agents. Patients with previous exposure to RAS-targeted therapy, exposure to thoracic radiotherapy within 2 months, interstitial lung disease, or untreated central nervous system metastases were excluded. Daraxonrasib was administered orally once daily in 21-day cycles at doses of 10 mg to 400 mg; the primary end point was safety, and secondary end points included investigator-assessed objective response rate, DOR, time to response, and PFS per RECIST 1.1 criteria.

Between June 22, 2022, and July 21, 2025, 137 patients with RAS-mutant NSCLC were enrolled, and 136 patients received daraxonrasib at 300 mg or less. Patients had received a median of 2 previous lines of therapy for metastatic disease (range, 0-7); 99% of patients had received previous platinum-based chemotherapy, and 99% of patients had received previous anti–PD-1 or anti–PD-L1 therapy. The most common RAS mutations were G12V (37%) and G12D (30%); key co-mutations included TP53 (53%), STK11 (20%), and KEAP1 (10%).

What were the response and survival outcomes with daraxonrasib across RAS mutation subgroups in NSCLC?

Among 32 patients treated at the 300-mg dose who had received previous first- or second-line platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy but not docetaxel, a confirmed response was observed in 41% (95% CI, 24%-59%); among the 28 patients in this group with RAS G12–mutant NSCLC, the confirmed response rate was 43% (95% CI, 24%-63%). At the 160-mg-to-220-mg dose level, the 6-month PFS rates were 65% (95% CI, 46%-78%) among patients with any RAS mutation and 69% (95% CI, 49%-82%) among those with RAS G12 mutations; the 6-month OS rates were 84% (95% CI, 67%-92%) and 81% (95% CI, 62%-91%) in these respective groups. In exploratory biomarker analyses of 57 patients assessed for STK11, KEAP1, and TP53 co-mutation status, confirmed responses were consistently observed across patients regardless of co-mutation status, although the study authors noted that the subgroup sizes were small.

What is the safety profile of daraxonrasib in previously treated NSCLC?

AEs of any grade occurred in 99% of the 136 patients in the safety population, and AEs of grade 3 or higher occurred in 54% of patients. Grade The most common 3 or 4 AEs included pneumonia (9%), diarrhea (9%), rash (8%), and anemia (5%); 4 grade 5 AEs were reported (dyspnea, pneumonia, and myocardial infarction at the 160-mg-to-220-mg doses, and a peripheral vascular disorder at the 300-mg dose). TRAEs of any grade occurred in 99% of patients, and TRAEs of grade 3 or higher occurred in 30% of patients; no grade 4 or 5 TRAEs occurred at the 160-mg-to-220-mg doses, whereas a grade 4 TRAE of pneumonitis occurred in 1 patient (2%) at the 300-mg dose and was managed with dose interruption and supportive care.

The most common any-grade AEs across the safety population, occurring in at least 20% of patients, were rash (90%), diarrhea (73%), nausea (62%), vomiting (54%), and mucositis or stomatitis (40%). AEs leading to dose modification or discontinuation were more frequent with the 300-mg dose (82% and 16%, respectively) than with the 160-mg-to-220-mg doses (71% and 10%, respectively), and the mean relative dose intensity was 75% at 300 mg compared with 88% at 160 mg to 220 mg.

What are the next steps for investigating daraxonrasib in NSCLC?

The 200-mg dose was selected for phase 3 evaluation on the basis of the efficacy, safety, and pharmacokinetic and pharmacodynamic data from the 160-mg-to-220-mg dose range, which was associated with a lower incidence of AEs and fewer dose modifications than the 300-mg dose while sustaining RAS pathway suppression. These findings support the ongoing phase 3 RASolve 301 trial (NCT06881784), which is evaluating daraxonrasib vs docetaxel as second-line therapy in patients with RAS-mutant NSCLC.²

The authors noted that the nonrandomized, phase 1/2 design and small sample sizes within individual RAS-mutation and co-mutation subgroups limit the precision of the RMC-6236-001 trial efficacy analyses, and that the exclusion of patients who had received previous RAS-targeted therapy limited enrollment of those with KRAS G12C–mutant disease.¹

“Emerging data suggest that both on-target RAS mutations and MAPK pathway reactivation may contribute to acquired resistance, although these findings remain preliminary and require further validation,” the authors concluded.

References

1. Arbour KC, Punekar S, Luo J, et al. Daraxonrasib for previously treated RAS-mutant non-small-cell lung cancer. N Engl J Med. 2026;395(9):882-893. doi:10.1056/NEJMoa2504059
2. Study of daraxonrasib (RMC-6236) in patients with RAS mutated NSCLC (RASolve 301) (RASolve 301). ClinicalTrials.gov. Updated August 27, 2026. Accessed September 3, 2026. https://clinicaltrials.gov/study/NCT06881784