A multiselective RAS inhibitor produced responses across RAS-mutant lung cancer

Design

phase 1-2 multicentre dose-escalation and dose-expansion study, safety primary endpoint

Population

136 patients with previously treated advanced RAS-mutant non-small-cell lung cancer, treated at ≤300 mg daily

Primary outcome

safety; objective response by RECIST 1.1 as secondary

Effect

response 31% (≤120 mg), 34% (160–220 mg), 37% (300 mg); grade ≥3 adverse events 54%, four grade 5 events

RAS mutations drive about 30% of non-small-cell lung cancer, and until recently only the G12C variant was druggable. Daraxonrasib is an oral tri-complex inhibitor that targets GTP-bound mutant and wild-type RAS across isoforms, which in principle reaches the much larger group of non-G12C mutations.

This phase 1-2 study escalated and expanded doses from 10 to 400 mg once daily in 21-day cycles, with safety as the primary endpoint. By the July 2025 data cut, 136 patients with previously treated advanced RAS-mutant disease had received 300 mg or less. Objective response was 31% at 120 mg or less, 34% at 160 to 220 mg and 37% at 300 mg.

The toxicity is not incidental. Adverse events of any grade occurred in 99% of patients, with rash, diarrhoea, nausea, vomiting and mucositis each in at least 30%. Grade 3 or higher events affected 54%, including pneumonia in 10%, diarrhoea in 9%, rash in 8% and anaemia in 5%, and there were four grade 5 events. A response rate in the thirties in previously treated disease is meaningful, and so is a one-in-two rate of severe toxicity.

For practice this is a signal rather than an option: it is a dose-finding study with an investigator-assessed response endpoint and no comparator. What it changes now is the value of knowing a patient's full RAS status rather than testing for G12C alone.

• Ensure RAS testing reports the specific variant, not just G12C positive or negative
• Counsel about rash, diarrhoea and mucositis as expected rather than possible effects
• Watch for pneumonia, which was the commonest grade 3 or higher event at 10%
• Treat this as trial-stage: response rate, not survival, and no control arm

Why it matters

It extends targeted therapy beyond the single RAS variant that has been actionable so far.

Don't overread it

This is a phase 1-2 study with no comparator arm — it establishes activity and toxicity, not benefit over existing options.

The statistics, in plain English

Objective response rate measures tumour shrinkage on imaging, not how long anyone lives — it is the standard early-phase signal and it routinely overstates clinical benefit. The apparent dose-response from 31% to 37% is across separate non-randomised groups, so it does not establish that a higher dose is better. Investigator assessment, rather than blinded central review, tends to inflate response rates.

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