Development

NEJM publishes daraxonrasib NSCLC data supporting Phase III program

Edited by Robert McTiernan··2 min read
NEJM publishes daraxonrasib NSCLC data supporting Phase III program

Revolution Medicines (Nasdaq: RVMD) has published updated Phase I/II data in the New England Journal of Medicine showing antitumor activity for daraxonrasib (Rasonque) in previously treated non-small cell lung cancer (NSCLC) driven by RAS mutations other than KRAS G12C.

The publication comes as Revolution advances the drug through the global Phase III RASolve 301 study and one week after the US FDA approved daraxonrasib in metastatic pancreatic adenocarcinoma, establishing the pan-RAS inhibitor as the company's first commercial product.

The NSCLC analysis comes from the Phase I/II RMC-6236-001 study, which enrolled 136 patients with previously treated RAS-mutant NSCLC excluding KRAS G12C. The efficacy analysis that informed Phase III development focused on 38 docetaxel-naïve patients treated with 160–220 mg once daily.

In that subgroup, daraxonrasib produced a confirmed objective response rate of 42% and disease control rate of 89%. Median progression-free survival was 8.3 months, while median overall survival reached 16.0 months at the July 2025 data cutoff. Grade 3 treatment-related adverse events occurred in 25% of patients, with rash and diarrhea the most common; no Grade 4 or Grade 5 treatment-related events were reported at those doses.

The results provide the clinical basis for RASolve 301, a randomized Phase III trial comparing daraxonrasib with docetaxel in previously treated locally advanced or metastatic RAS-mutant NSCLC. That study will test whether the activity seen in the relatively small Phase I/II subgroup translates into a survival advantage against an established second-line treatment.

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Daraxonrasib is an oral, noncovalent tri-complex inhibitor designed to suppress active RAS signaling across multiple oncogenic variants, including KRAS G12D, G12V, and G12R. That differentiates it from approved KRAS G12C inhibitors such as sotorasib and adagrasib, as well as mutation-specific programs targeting individual RAS variants.

The broader targeting strategy could expand the addressable population beyond KRAS G12C, but the Phase I/II dataset remains early and non-randomized. The strongest efficacy estimates also come from a 38-patient subgroup selected to match the dose range and treatment history being carried forward into Phase III.

Competition is advancing in some of the same genetically defined populations. Astellas is evaluating the KRAS G12D-targeted protein degrader setidegrasib (ASP3082) against docetaxel in Phase III NSCLC, while other developers are pursuing mutation-specific KRAS inhibitors and degraders.

For Revolution, the NEJM publication adds peer-reviewed support for a second major tumor opportunity for daraxonrasib following its pancreatic cancer approval. The more consequential test will come from RASolve 301, where a randomized comparison with docetaxel will determine whether pan-RAS inhibition can improve outcomes across the broader non-G12C RAS-mutant NSCLC population.

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