Daraxonrasib Yields Activity in Previously Treated RAS-Mutant NSCLC

Daraxonrasib (Rasonque), an oral RAS(ON) multiselective inhibitor, demonstrated antitumor activity along with a manageable safety profile in patients with previously treated advanced RAS-mutant non–small cell lung cancer (NSCLC), according to results from the phase 1/2 RMC-6236-001 trial (NCT05379985) published in the New England Journal of Medicine.¹

What was the efficacy of daraxonrasib in RAS-mutant NSCLC?

Among 136 patients treated with daraxonrasib at doses of 300 mg or less, the objective response rate (ORR) was 31% (95% CI, 14%-52%) at 120 mg or less, 34% (95% CI, 22%-47%) at doses of 160 to 220 mg, and 37% (95% CI, 24%-52%) at 300 mg. In the expansion cohorts, the disease control rate was 89% (95% CI, 75%-97%) among patients with any RAS mutation (n = 38) and 88% (95% CI, 72%-97%) among those with RAS G12 mutations (n = 33) and the median duration of response (DOR) was 11.5 months (95% CI, 4.6-not estimable) and not evaluable (NE; 95% CI, 4.6-NE). An estimated 48% (95% CI, 19%-72%) and 51% (95% CI, 21%-75%) of responding patients maintained a response at 18 months. Based on the totality of the data, including a dose range with overlapping exposures at 160 to 220 mg, the 200-mg dose was selected for phase 3 evaluation.

What was the safety profile of daraxonrasib?

Adverse events (AEs) of any grade occurred in 99% of patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis each occurring in at least 30% of patients. Grade 3 or higher AEs were reported in 54% of patients, which included pneumonia (10%), diarrhea (9%), rash (8%), and anemia (5%); 4 grade 5 AEs occurred.

Most treatment-related AEs were grade 1 or 2 among patients receiving 160 to 220 mg. The authors reported that rash and gastrointestinal symptoms were the most common severe treatment-related AEs and were generally manageable and that prophylaxis is recommended in phase 3 trials to limit grade 3 events such as rash.

“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 [AEs] of grade 3 or higher, regardless of attribution, in 54% and treatment-related [AEs] of grade 3 or higher in 30%, along with a response in more than 30% of patients,” lead author Kathryn C. Arbour, MD, a thoracic medical oncologist at the David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center, wrote in the publication with study coinvestigators.¹ “The results are notable in a treatment landscape characterized by limited options with modest clinical benefit and substantial toxic effects. These findings highlight the therapeutic potential of RAS(ON) multiselective inhibition.”

What is the trial design of RMC-6236-001?

RMC-6236-001 is a phase 1/2, multicenter, dose-escalation and dose-expansion study evaluating daraxonrasib in patients with previously treated advanced RAS-mutant NSCLC. Patients received daraxonrasib at 10 to 400 mg orally once daily in 21-day cycles, with the recommended phase 2 dose identified using a Bayesian optimal interval design. Expansion cohorts of patients with KRAS G12–mutant NSCLC received daraxonrasib at 120 mg, 200 mg, or 300 mg. As of the July 21, 2025, data cutoff, 136 patients treated at doses of 300 mg or less were evaluated for safety and efficacy; the median age was 66 years.

The primary end point of the study was safety. Secondary end points included investigator-assessed ORR and DOR by RECIST v1.1 criteria; overall survival and biomarker analyses were exploratory.

The study investigators noted that results should be interpreted with caution due to the trial’s phase 1/2, nonrandomized design. They also noted that small sample sizes within individual RAS mutation categories and STK11, KEAP1, and TP53 comutation subgroups limit the scope of the efficacy analyses.

What is daraxonrasib's regulatory context?

Daraxonrasib is an oral RAS(ON) multiselective, tricomplex inhibitor of guanosine triphosphate–bound mutant and wild-type RAS protein isoforms. In August 2026, the FDA approved daraxonrasib for patients with previously treated metastatic pancreatic ductal adenocarcinoma based on data from the RASolute 302 trial (NCT06625320).²

“We [took] what was called an undruggable target for many, many years, and now we have an effective drug against it,” Nicholas Hornstein, MD, PhD, a gastrointestinal oncologist at Northwell Health and a 2024 American Society of Clinical Oncology Young Investigator Award winner, stated in an interview with CancerNetwork^® regarding daraxonrasib’s approval in pancreatic cancer. “We’ve also now seen the first-ever effective systemic therapy for pancreas cancer that is not a chemotherapy. Overall, some major advances in the field, and this is something that is very exciting.”

References

1. Arbour KC, Punekar S, Luo J, et al; RMC-6236-001 Investigators. 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. FDA approves first in class targeted therapy for metastatic pancreatic cancer. News release. FDA. August 26, 2026. Accessed September 3, 2026. https://tinyurl.com/4dt6cwnv