A targeted oral agent already approved by the FDA for metastatic pancreatic cancer, daraxonrasib (Rasonque), demonstrated antitumor activity in a phase 1–2 study of adults with previously treated, advanced non–small cell lung cancer (NSCLC) harboring RAS mutations. The trial, reported in the New England Journal of Medicine, enrolled patients whose disease had progressed after prior therapy or who had experienced unacceptable side effects on earlier treatments.
Investigators evaluated daily daraxonrasib doses ranging from 10 mg to 400 mg. Due to frequent dose modifications at the 400 mg level, the primary analysis was limited to 136 participants who received 300 mg or less. The study’s primary focus was safety; investigators also measured tumor response and survival endpoints.
Across dose cohorts, more than 30% of participants had objective tumor shrinkage. Reported response rates were 31% for participants taking 120 mg or less, 34% for those on 160–220 mg, and 37% for the 300 mg group. These results indicate consistent antitumor activity across the evaluated dose range in this early‑phase population of RAS‑mutant NSCLC.
An exploratory analysis examined 38 participants who received 160–220 mg daily. This subgroup had previously been treated with chemotherapy and immunotherapy but had not received the chemotherapy agent docetaxel, which investigators plan to use as the comparator in a forthcoming phase 3 trial.
In the 160–220 mg subgroup, 42% experienced tumor shrinkage and 89% achieved disease control (tumor shrinkage or no growth for at least four weeks). Among those whose tumors responded, the median duration of response was 11.5 months. Median progression‑free survival in this exploratory cohort was 8.3 months, and median overall survival was 16 months.
Because the study was not randomized and lacked a direct comparator arm, researchers caution that these survival figures cannot establish that daraxonrasib extends survival compared with existing treatments. The investigators have proposed a randomized phase 3 trial to compare daraxonrasib directly with a standard chemotherapy option.
Nearly all participants experienced at least one adverse event during the study, although not every event was judged related to daraxonrasib. More than half of participants had grade 3 or higher adverse events. The most frequently reported severe events included pneumonia, diarrhea, rash, and anemia. Investigators attributed grade ≥3 events to daraxonrasib in 30% of participants.
Common, generally manageable side effects included rash, mouth sores (mucositis), diarrhea, nausea, and vomiting. Many toxicities were addressed by dose modifications or supportive care measures.
The RAS gene family—KRAS, NRAS, and HRAS—encodes proteins that regulate cell growth and division. Mutations in RAS can lock signaling in an active state and drive cancer cell proliferation and spread. NSCLC accounts for roughly 85% of lung cancer cases, and about 30% of NSCLC tumors harbor RAS mutations.
Historically, RAS proteins have been challenging to target pharmacologically. Recent therapies address select mutations such as KRAS G12C, but many RAS alterations currently lack targeted options. Daraxonrasib is described as a RAS(ON) multiselective inhibitor: rather than binding a single inactive RAS variant, it is designed to inhibit active RAS across multiple proteins and mutations. This broader mechanism could potentially expand targeted therapy to patients with diverse RAS‑driven cancers.
Independent experts quoted in the report described the findings as encouraging but emphasized caution. A medical oncologist noted the potential for daraxonrasib to provide another treatment option that may improve patients’ quality and length of life, while also stressing the importance of direct comparison with current standards of care in a phase 3 randomized trial.
A clinical oncology pharmacist highlighted that most existing KRAS‑targeted drugs act on a single mutation, whereas daraxonrasib’s strategy of targeting the active form of multiple RAS proteins could make targeted therapy available to people whose RAS mutations currently have few or no approved options. Both experts underlined that promising early results do not guarantee a new standard of care without confirmatory randomized data.
In this phase 1–2 study, daraxonrasib produced tumor responses in a substantial minority of patients with previously treated, RAS‑mutant NSCLC and showed similar activity across several dose levels. Toxicities were common, including a notable rate of grade 3 or higher events, and were managed in many cases with dose adjustments.
Because the trial was small and nonrandomized, it cannot determine whether daraxonrasib improves survival compared with established therapies. The planned randomized phase 3 trial, which will compare daraxonrasib with a standard chemotherapy agent, is needed to establish comparative efficacy and safety before the drug could be adopted as a treatment option for RAS‑mutant NSCLC.