A reappraisal argues the fezolinetant neoplasm signal was dismissed too readily

Design

Critical review of phase 3 safety data and regulatory reasoning

Population

SKYLIGHT phase 3 programme of fezolinetant for menopausal vasomotor symptoms

Primary outcome

Exposure-adjusted incidence of non-benign neoplasms

Effect

RR 6.6 (95% CI 0.9 to 51.3) at 45 mg vs placebo; dose-related but not significant

Fezolinetant, a neurokinin-3 receptor antagonist for menopausal hot flushes, showed more neoplasms in drug-treated women than placebo in its phase 3 programme. Regulators judged this to be chance, partly because no plausible mechanism was identified.

This analysis points out that the imbalance rose with dose, that most of the literature cited by regulators concerned a different receptor, and that several mechanisms could accelerate cancers already present. It calls for structured post-authorisation surveillance.

The numbers are small and the interval is wide, so harm is not shown. The appropriate response is careful reporting, not withdrawal of a licensed treatment.

• Non-benign neoplasm rates were 0.2, 0.7 and 1.2 per 100 subject-years on placebo, 30 mg and 45 mg.
• The relative risk at the licensed dose was 6.6, with an interval from 0.9 to 51.3.
• Most references used to dismiss the signal concerned a different receptor, NK1.
• The authors propose mechanisms that would accelerate existing lesions rather than cause new ones.
• Regulators have not changed the label on this basis.

Why it matters

Regulators set aside a dose-related imbalance as chance; this analysis argues the mechanistic reasoning behind that was flawed.

Don't overread it

The imbalance was not statistically significant and rests on few events; this is an argument for surveillance, not evidence of harm.

The statistics, in plain English

A relative risk of 6.6 sounds large, but the interval from 0.9 to 51.3 includes no effect, because there were only a handful of events. A dose trend adds weight but does not settle it.

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