A pan-RAS inhibitor produces responses in RAS-mutant lung cancer, at a real toxicity price

Design

Phase 1–2 multicentre dose-escalation and dose-expansion study, single-arm, primary endpoint safety

Population

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

Primary outcome

Safety; objective response by RECIST 1.1 was a secondary endpoint

Effect

Objective response 31% at 120 mg or less, 34% at 160–220 mg, 37% at 300 mg; grade 3 or higher adverse events 54%

RAS mutations drive about 30% of non-small-cell lung cancer, and most of them are not G12C — so the approved KRAS G12C inhibitors leave the majority untreated. Daraxonrasib is an oral multiselective inhibitor of the active, GTP-bound form of mutant and wild-type RAS. In a phase 1–2 dose-escalation and expansion study, 136 previously treated patients with advanced RAS-mutant lung cancer received 300 mg daily or less. Objective response was 31% at doses of 120 mg or less, 34% at 160 to 220 mg, and 37% at 300 mg.

The safety profile is the part to weigh. 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 occurred in 54%: pneumonia 10%, diarrhoea 9%, rash 8%, anaemia 5%. Four grade 5 events occurred. Inhibiting wild-type as well as mutant RAS is the likely explanation for the mucocutaneous and gastrointestinal burden, and it is not a profile that suits a frail patient.

Read this as promising and preliminary, in that order. The primary endpoint was safety; there is no control arm, response was investigator-assessed, and duration of response and survival are not established. What it does show is that a target long considered undruggable produces responses across RAS isoforms in a third of pretreated patients, which is why the randomised trials matter more than this one. Nothing here changes what you prescribe today, and the drug is not available in India outside a trial.

• Test broadly for RAS, not only KRAS G12C — most RAS-mutant lung cancer is not G12C.
• Treat the response rate as investigator-assessed and uncontrolled; there is no comparator arm.
• Expect mucocutaneous and gastrointestinal toxicity if a patient enters a trial of this class.
• Grade 3 or higher toxicity in 54% makes performance status central to eligibility.
• Availability is trial-only; there is no CDSCO approval to discuss with a patient.

The statistics, in plain English

Response rates from a single-arm dose-finding study carry no comparison, so the right reference is what pretreated RAS-mutant lung cancer usually achieves on chemotherapy — roughly 10 to 20% — rather than any figure inside this trial. The apparent dose-response, from 31% to 37% across bands, spans overlapping small groups and should not be read as evidence that higher doses work better. And with safety as the primary endpoint, the efficacy numbers are secondary outcomes in a study not designed to estimate them precisely. What survives all that is a qualitative conclusion: the drug is active, and it needs a randomised trial to say how much.

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