Daraxonrasib for Previously Treated RAS-Mutant Non–Small-Cell Lung Cancer

Author(s): Kathryn C. Arbour, M.D.^1,2; Salman Punekar, M.D.³; Jia Luo, M.D.^4,5,6; Melissa Johnson, M.D.⁷; Alexander Spira, M.D., Ph.D.⁸; Benjamin Herzberg, M.D.⁹; Alexander Starodub, M.D.¹⁰; David Sommerhalder, M.D.¹¹; Joel Randolph Hecht, M.D.¹²; Ignacio Garrido-Laguna, M.D.¹³; Minal Barve, M.D.¹⁴; Sai-Hong Ignatius Ou, M.D.¹⁵; Sumit Kar, Ph.D.¹⁶; Lei Bao, Ph.D.¹⁶; Lin Tao, M.S.¹⁶; Rashmi Vora, M.B., B.S.¹⁶; Aparna Hegde, M.D.¹⁶; Andreas Saltos, M.D.¹⁷; Nilofer S. Azad, M.D.¹⁸; David S. Hong, M.D.¹⁹; the RMC-6236-001 Investigators*;

Source: DOI: 10.1056/NEJMoa2504059

Dr. Anjan Patel's Thoughts

This feels like the first real crack in the "undruggable" non-G12C RAS wall in lung cancer: a pan-RAS(ON) inhibitor with responses across G12D, G12V, and other alleles in patients who had already received platinum and immunotherapy. At the 160–220 mg range (the phase 3 dose is 200 mg), patients who hadn't yet received docetaxel had a 42% response rate, median progression-free survival (PFS) of 8 mos, and median overall survival (OS) of 16 mos, which looks well ahead of what we expect from docetaxel, though that's a cross-trial comparison. The catch is tolerability: about half had grade 3 or higher events, 9 in 10 got rash, and most got diarrhea, so rash prophylaxis and proactive GI management will matter just as it does on PDAC. The randomized RASolve 301 trial against docetaxel is the one to watch before this moves into practice.

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 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 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 least 5% of patients; four grade 5 adverse events occurred. The percentage of patients who had an objective response was 31% with daraxonrasib a dose of 120 mg or less, 34% doses of 160 to 220 mg, and 37% a dose of 300 mg.

CONCLUSIONS

Among patients with previously treated metastatic RAS-mutant NSCLC receiving daraxonrasib 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.)

Author Affiliations

¹Memorial Sloan Kettering Cancer Center, New York; ²Weill Cornell Medical College, New York; ³NYU Langone Health, New York; ⁴Dana–Farber Cancer Institute, Boston; ⁵Brigham and Women’s Hospital, Boston; ⁶Harvard Medical School, Boston; ⁷Sarah Cannon Research Institute, Nashville; ⁸NEXT Oncology Virginia, Virginia Cancer Specialists Research Institute, Fairfax; ⁹Columbia University, New York; ¹⁰The Christ Hospital, Cincinnati; ¹¹NEXT Oncology, San Antonio, TX; ¹²David Geffen School of Medicine UCLA, Los Angeles; ¹³Huntsman Cancer Institute, University of Utah, Salt Lake City; ¹⁴Mary Crowley Cancer Research, Dallas; ¹⁵University of California, Irvine, Irvine; ¹⁶Revolution Medicines, Redwood City, CA; ¹⁷Moffitt Cancer Center, Tampa, FL; ¹⁸Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore; ¹⁹M.D. Anderson Cancer Center, Houston

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