Daraxonrasib Shows Antitumor Activity in RAS-Mutant NSCLC

Daraxonrasib (Rasonque) demonstrated antitumor activity in patients with previously treated, advanced RAS-mutant non–small cell lung cancer (NSCLC), according to results published from the phase 1/2 RMC-6236-001 trial (NCT05379985) published in The New England Journal of Medicine (NEJM).¹

Findings from the multicenter dose-escalation and -expansion study that among 136 patients with RAS-mutant NSCLC treated with daraxonrasib at doses of 300 mg or less once daily, investigator-assessed objective response rates per RECIST v1.1 were 31% at doses of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg, as of a data-cutoff date of July 21, 2025.

“RAS mutations are among the most common oncogenic drivers in lung cancer, occurring in approximately 30 percent of cases. Targeted RAS inhibition has demonstrated clinical benefit in patients with RAS G12C [NSCLC] following initial treatment with chemotherapy and immunotherapy, but there are no targeted therapies for patients with other RAS tumor mutations,” said Alan Sandler, MD, chief development officer at Revolution Medicines, said in a news release. “Together with the recent FDA approval of [daraxonrasib] in metastatic pancreatic cancer, the data reported in the NEJM publication provide additional clinical validation of our broad RAS(ON) multi-selective and mutant-selective approach across major RAS-driven cancers.”

Trial Design

RMC-6236-001 enrolled patients with previously treated advanced RAS-mutant solid tumors to receive daraxonrasib, an oral RAS(ON) multiselective, tri-complex inhibitor of guanosine triphosphate-bound mutant and wild-type RAS protein isoforms, in doses of 10 to 400 mg orally once daily in 21-day cycles. The primary end point was safety; secondary end points included investigator-assessed objective response and duration of response. The 136 patients with NSCLC evaluated at doses of 300 mg or less had second-line or later NSCLC with tumors carrying RAS mutations other than KRAS G12C, and disease that had progressed following, or was intolerant to, platinum-based chemotherapy and anti–PD-(L)1 therapy.

Safety Findings

Across the full 136-patient population treated at doses of 300 mg or less, adverse events (AEs) of any grade, regardless of attribution, were reported 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 occurred in 54% of patients, most commonly pneumonia (10%), diarrhea (9%), rash (8%), and anemia (5%); 4 grade 5 AEs were reported.

According to the company, in a subgroup of 38 docetaxel-naive patients treated at doses of 160 mg to 220 mg who had received first- or second-line platinum-based chemotherapy and anti–PD-(L)1 therapy, grade 3 treatment-related AEs (TRAEs) occurred in 25% of patients, most commonly rash (8%) and diarrhea (3%), with no grade 4 or 5 TRAEs reported in this dose range.

Efficacy in the Docetaxel-Naive Subgroup

In the docetaxel-naive subgroup, the confirmed objective response rate was 42% (95% CI, 26%-59%), and the disease control rate was 89% (95% CI, 75%-97%). Median progression-free survival (PFS) in this subgroup was 8.3 months (95% CI, 4.0-12.5), and median overall survival (OS) was 16.0 months (95% CI, 9.5-not estimable).

Broader Development Context

The results support the design and initiation of RASolve 301 (NCT06881784), an ongoing global, randomized, open-label phase 3 trial comparing daraxonrasib with docetaxel in patients with previously treated, locally advanced or metastatic RAS-mutant NSCLC. Daraxonrasib received accelerated FDA approval in adults with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy or who are not candidates for multiagent systemic therapy; that approval was reported previously.³

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. New England Journal of Medicine Publishes Phase 1/2 Clinical Data on Revolution Medicines' RASONQUE™ (daraxonrasib) in Metastatic Non-Small Cell Lung Cancer. News release. Revolution Medicines, Inc. September 2, 2026. Accessed September 3, 2026. https://tinyurl.com/43wnsj6h

3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA August 26, 2026. Accessed September 3, 2026. https://tinyurl.com/457vwtek