Reassessing the Neoplasm Signal with Fezolinetant: Regulatory Inference, Mechanistic Plausibility, and the Case for Proactive Pharmacovigilance.

Fezolinetant, the first neurokinin-3 receptor (NK3R) antagonist licensed for moderate-to-severe vasomotor symptoms associated with menopause, carries an unresolved neoplasm signal. An imbalance in neoplasm events across the SKYLIGHT phase III programme, raised in 2023, has been set aside by regulators as a chance finding lacking a plausible mechanism. We reassess that inference on three grounds. First, exposure-adjusted incidence of non-benign neoplasms rises across placebo, 30 mg and 45 mg, at 0.2, 0.7 and 1.2 per 100 subject-years, giving a relative risk at the licensed dose of 6.6 (95% confidence interval 0.9-51.3); a published recalculation gives 7.83 by counting 13 organ-class entries rather than 11 affected participants. The imbalance is dose related but not statistically significant. Second, of the 15 references mobilised in the European regulatory literature review to support that position, 11 concern the neurokinin-1 receptor or substance P rather than NK3R, two report NK3R expression in oral squamous cell carcinoma without administering an antagonist, one contains no neoplasm data and one alone administers an NK3R antagonist, finding that it reduced tumour burden. The pharmacology of the two receptors does not permit the extrapolation. Third, four mechanisms merit evaluation: loss of KISS1-mediated metastasis suppression and dormancy control, compensatory neurokinin-1 receptor activation by unbound neurokinin B, loss of anti-angiogenic restraint and acceleration of lesions already present. None requires de novo carcinogenesis, so the short-latency argument is not decisive. We recommend structured post-authorisation surveillance, a periodic independent safety review and re-examination of the mechanistic rationale.