Daraxonrasib Shows Antitumor Activity in Previously Treated RAS-Mutant Non-Small-Cell Lung Cancer
- Immunotherapy has improved outcomes for many patients with non-small cell lung cancer, but the majority of these cancers eventually progress.
- Because nearly all individuals taking daraxonrasib encountered some side effects, careful dose tuning is vital to keep these reactions to a minimum.
Daraxonrasib, an oral RAS inhibitor developed by Revolution Medicines, demonstrated initial antitumor activity and durable responses in pretreated patients with RAS-mutant non-small-cell lung cancer, according to a Phase 1/2 clinical trial published on September 3, 2026, in The New England Journal of Medicine. RAS mutations drive approximately 30 percent of non-small-cell lung cancer cases, presenting significant treatment challenges once standard immunotherapy and platinum-based chemotherapy fail.
According to the New England Journal of Medicine study, daraxonrasib acts as an oral RAS(ON) multiselective, tri-complex inhibitor targeting guanosine triphosphate-bound mutant and wild-type RAS protein isoforms. Led by investigators including David Hong, deputy chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, the multicenter clinical trial evaluated patients administered daraxonrasib in doses ranging from 10 mg to 400 mg orally once daily in 21-day cycles. Data through the July 21, 2025 cutoff date covered 136 patients with non-small-cell lung cancer treated at doses of 300 mg or less.
Clinical Efficacy and Response Rates
Antitumor activity was observed in more than 30 percent of evaluated patients receiving daraxonrasib at doses of 300 mg or less, according to findings published in The New England Journal of Medicine. The percentage of patients achieving an objective response reached 31 percent at doses of 120 mg or less, 34 percent at doses between 160 and 220 mg, and 37 percent at a 300 mg dose.
According to MD Anderson Cancer Center reporting, the most clinically relevant results emerged within a cohort of 38 patients with non-small-cell lung cancer treated with 160 to 220 mg of daraxonrasib. These individuals had previously received platinum-based chemotherapy and immunotherapy but had not yet received docetaxel, the common standard of care for progressive RAS-mutant disease. Within this specific cohort, the objective response rate hit 42 percent, accompanied by a median duration of response of 11.5 months. Median progression-free survival reached 8.3 months, and median overall survival stood at 16 months.
By comparison, historical studies examining docetaxel chemotherapy in this exact setting have reported response rates of 9 to 14 percent, a median progression-free survival of 3 to 4.5 months, and a median overall survival of approximately 9 to 12 months, according to MD Anderson data.
Immunotherapy has improved outcomes for many patients with non-small cell lung cancer, but the majority of these cancers eventually progress. Given that current therapeutic alternatives often provide limited clinical benefit accompanied by heavy toxicities, these preliminary findings bring positive news.
David Hong, M.D., The University of Texas MD Anderson Cancer Center
Safety Profile and Adverse Events
Adverse events of any grade, regardless of attribution, occurred in 99 percent of patients treated at doses of 300 mg or less, as detailed in the New England Journal of Medicine report. The most frequent any-grade side effects included rash, diarrhea, nausea, vomiting, and mucositis or stomatitis, each affecting at least 30 percent of participants.
Adverse events of grade 3 or higher affected 54 percent of patients in the overall safety population. Pneumonia occurred in 10 percent of patients, diarrhea in 9 percent, rash in 8 percent, and anemia in 5 percent, with four grade 5 adverse events recorded overall. At the specific recommended Phase 3 dose range of 160 to 220 mg, 51 percent of patients experienced an adverse effect of grade 3 or higher, leading to dose modifications in 71 percent of patients and treatment discontinuation in 10 percent, according to MD Anderson data. Within this recommended dose cohort, rash affected 90 percent of patients overall while remaining grade 3 or above in 8 percent, and gastrointestinal issues including diarrhea, nausea, and vomiting occurred in 73 percent, 62 percent, and 54 percent of patients respectively, with each individual gastrointestinal toxic effect remaining under 10 percent at grade 3 or above.
Because nearly all individuals taking daraxonrasib encountered some side effects, careful dose tuning is vital to keep these reactions to a minimum. Still, the toxicities are largely manageable compared to the alternatives available.
David Hong, M.D., The University of Texas MD Anderson Cancer Center
Next Steps and Ongoing Phase 3 Trials
Initial data from the RMC-6236-001 trial were presented at the 2025 European Lung Congress, prompting the initiation of the Phase 3 RASolve 301 clinical trial, according to MD Anderson disclosures. At MD Anderson, the Phase 3 trial is led by Ferdinandos Skoulidis, associate professor of Thoracic/Head and Neck Medical Oncology, with initial data anticipated in 2027. The clinical trial program is funded by Revolution Medicines.