Daraxonrasib produced responses in more than 30% of patients with previously treated advanced RAS-mutant non–small cell lung cancer (NSCLC), with activity observed across multiple RAS mutations in a phase I/II study. Results from Kathryn C. Arbour, MD, David S. Hong, MD, and colleagues were published in The New England Journal of Medicine.
RAS mutations occur in approximately 30% of patients with NSCLC, but most RAS-mutant tumors have mutations for which no targeted therapies are approved. Daraxonrasib (RMC-6236) is an oral RAS(ON) inhibitor designed to target active RAS across multiple mutations, rather than a single RAS variant.
The need for additional options in this patient population is particularly acute after platinum-based chemotherapy and immune checkpoint inhibition, when docetaxel-based therapy remains a standard of care but has shown modest clinical benefit.
Study Details
RMC-6236-001 (ClinicalTrials.gov identifier NCT05379985) is an open-label, multicenter, dose-escalation and dose-expansion study of daraxonrasib in patients with advanced RAS-mutant solid tumors. The current analysis included adults with previously treated advanced NSCLC harboring KRAS, NRAS, or HRAS mutations at G12, G13, or Q61, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients had disease progression during or unacceptable toxicity with previous platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy.
Patients received oral daraxonrasib once daily in 21-day cycles at doses ranging from 10 to 400 mg. The primary endpoint was safety, with objective response, duration of response, time to response, and progression-free survival among the efficacy endpoints. The maximum tolerated dose was not reached, but frequent dose reductions and interruptions made the 400 mg dosage difficult to maintain.
The analysis included 136 patients who received doses of 300 mg or less. Median age was 66 years, and patients had received a median of two previous lines of therapy for metastatic disease. Nearly all had previously received platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy. The most common mutations were RAS G12V in 37% and RAS G12D in 30%.
Key Findings
Confirmed objective responses were observed in 31% of patients receiving daraxonrasib at doses of 120 mg or less, 34% of those receiving 160 to 220 mg, and 37% of those receiving 300 mg.
In a post hoc analysis of 38 patients who had received one or two previous lines of treatment, including platinum-based chemotherapy and immunotherapy but not docetaxel, 42% responded to 160 to 220 mg of daraxonrasib. Responses lasted a median of 11.5 months, and 89% of patients achieved disease control.
In this subgroup, median progression-free survival was 8.3 months, and median overall survival was 16 months. The investigators noted that previous studies of docetaxel have reported shorter survival but cautioned that the results cannot be directly compared across trials.
“The results are notable in a treatment landscape characterized by limited options with modest clinical benefit and substantial toxic effects,” the investigators wrote.
Grade 3 or higher adverse events occurred in 54% of the 136 patients, including treatment-related events in 30%. The most common adverse events overall were rash, diarrhea, nausea, vomiting, and stomatitis.
Side effects increased with the dose. At 160 to 220 mg, 51% of patients had grade 3 or higher adverse events, including treatment-related events in 25%. No grade 4 or 5 treatment-related events occurred at these doses. At 300 mg, 65% of patients had grade 3 or higher adverse events, and 75% required a dose modification because of treatment-related side effects, compared with 47% at 160 to 220 mg.
“The response to daraxonrasib therapy was encouraging and was similar among patients receiving doses of 160 to 220 mg and those receiving 300 mg; the responses were durable and the benefit–risk profile was favorable,” the investigators wrote.
Based on the efficacy, safety, and pharmacokinetic and pharmacodynamic findings, 200 mg was selected for further evaluation in phase III trials.
The authors cautioned that the study was nonrandomized and that small mutation-specific and co-mutation subgroups precluded firm conclusions. Daraxonrasib at 200 mg is now being evaluated against docetaxel in the randomized phase III RASolve 301 trial (NCT06881784).
Dr. Hong, of The University of Texas MD Anderson Cancer Center, and Dr. Arbour, of Memorial Sloan Kettering Cancer Center, are corresponding authors of the article.
DISCLOSURE: The study was funded by Revolution Medicines. Disclosure forms provided by the authors are available at nejm.org.
