Daraxonrasib, a pan-RAS inhibitor, produced responses in about a third of pretreated RAS-mutant NSCLC

Design

Phase 1–2, multicentre dose-escalation and expansion study

Population

136 patients with previously treated advanced RAS-mutant NSCLC

Primary outcome

Safety; secondary objective response rate

Effect

ORR 31–37% by dose; grade ≥3 adverse events 54%

Daraxonrasib (RMC-6236) is an oral RAS(ON) multi-selective inhibitor that binds the active, GTP-bound form of mutant and wild-type RAS — unlike sotorasib and adagrasib, which target only KRAS G12C. In this phase 1–2 dose-escalation and expansion study, 136 patients with previously treated advanced RAS-mutant NSCLC received doses up to 300 mg daily.

Objective responses occurred in 31% at 120 mg or less, 34% at 160–220 mg and 37% at 300 mg. Adverse events were near-universal (99%), with rash, diarrhoea, nausea, vomiting and stomatitis in at least 30%. Grade 3 or higher events occurred in 54%, including pneumonia in 10%; there were four grade 5 events.

RAS mutations drive about 30% of NSCLC, and most are not G12C. A single agent with activity across RAS variants would widen targeted therapy considerably. But this is an early, uncontrolled study with a substantial toxicity burden; randomised trials are needed.

• Test advanced NSCLC for the full range of RAS mutations, not only KRAS G12C, as trial options expand.
• Daraxonrasib is investigational; refer eligible patients to trials.
• Rash, diarrhoea and mucositis are the dominant toxicities of this class — plan supportive care.
• Grade 3+ toxicity in over half means careful patient selection.

Why it matters

It points to targeted therapy for the majority of RAS-mutant lung cancers that G12C inhibitors cannot reach.

Don't overread it

Phase 1–2, uncontrolled, response-rate data only — no survival comparison against standard therapy.

The statistics, in plain English

Response rates without a control arm cannot show that patients live longer; they only show that tumours shrank in about one in three.

Read the rest in the app

You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.

Get Daily Doctor — free

Scan to keep reading on your phone. No account needed to start.