Daraxonrasib for Previously Treated RAS

Daraxonrasib for Previously Treated RAS-Mutant Non–Small-Cell Lung Cancer Published September 2, 2026 N Engl J Med 2026;395:882-893 DOI: 10.1056/NEJMoa2504059 Abstract Background RAS mutations, as a group, are the most common oncogenic drivers of non–small-cell lung cancer (NSCLC), and they occur in approximately 30% of patients. Whether daraxonrasib (RMC-6236) — an oral RAS(ON) multiselective, tri-complex inhibitor of guanosine triphosphate–bound mutant and wild-type RAS protein isoforms — is safe and effective in patients with RAS-mutant NSCLC is unknown. Methods In this phase 1–2, multicenter, dose-escalation and dose-expansion study of daraxonrasib, we enrolled patients with previously treated advanced RAS-mutant NSCLC and administered daraxonrasib 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 (complete or partial response) and the duration of response, with response assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results As of the data-cutoff date of July 21, 2025, a total of 136 patients with NSCLC who had been enrolled and treated with daraxonrasib at doses of 300 mg or less had been evaluated for safety and efficacy. Adverse events of any grade occurring with a dose of 300 mg or less, regardless of attribution, were reported in 99% of the patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis occurring in at least 30% of patients. Adverse events of grade 3 or higher were reported in 54% of the patients, with pneumonia (in 10%), diarrhea (in 9%), rash (in 8%), and anemia (in 5%) occurring in at least 5% of patients; four grade 5 adverse events occurred. The percentage of patients who had an objective response was 31% with daraxonrasib at a dose of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg. Conclusions Among patients with previously treated metastatic RAS-mutant NSCLC receiving daraxonrasib at a dose of 300 mg or less daily, 54% had adverse events of grade 3 or higher, and antitumor activity was reported in more than 30%. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.) Are you a member of an institution such as a university or hospital?Learn more about Institutional Access Notes A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Supported by Revolution Medicines. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the participating patients, their families, and the clinicians and research staff, as well as Samantha Santangelo, Ph.D., of Nucleus Global, an Inizio Company, for medical writing and editorial assistance with an earlier version of the manuscript, funded by Revolution Medicines. Supplementary Material Information & Authors Information Published In Copyright Copyright © 2026 Massachusetts Medical Society. All rights reserved. For personal use only. Any commercial reuse of NEJM Group content requires permission. History Published online: September 2, 2026 Published in issue: September 3, 2026 Topics Authors Metrics & Citations Metrics Altmetrics Citations Export citation Select the format you want to export the citation of this publication.