Vismodegib
Trade name: Erivedge. Smoothened (SMO) inhibitor. ATC L01XJ01.
Vismodegib is the first-in-class oral smoothened (SMO) inhibitor of the hedgehog signalling pathway, the central oncogenic driver in basal cell carcinoma. It is EMA-licensed for locally advanced or metastatic BCC where surgery and radiotherapy are not appropriate, but NICE did not recommend it for routine NHS use in TA489 (2017) — any UK use is off-pathway via individual funding request (IFR) or specialist commissioning. Side-effect profile (alopecia, dysgeusia, muscle cramps, weight loss) limits long-term tolerance.
Mechanism
Hedgehog signalling is constitutively activated in >90% of BCCs, most commonly through PTCH1 loss-of-function (sporadic and Gorlin syndrome) or SMO activating mutations. Vismodegib binds SMO and blocks downstream GLI transcription factor activation, reversing the oncogenic signal.
Indications and UK access
EMA-licensed indications:
- Symptomatic metastatic BCC (mBCC) — exceptionally rare.
- Locally advanced BCC (laBCC) not amenable to surgery or radiotherapy.
- In Gorlin syndrome — to reduce tumour burden where surgery is not feasible (off-label / case-by-case).
NICE TA489 (2017): not recommended for routine NHS use. Any UK use is off-pathway via individual funding request (IFR) or specialist commissioning — particularly relevant in Gorlin syndrome where surgical burden is high. Confirm the access route with your local commissioner and skin-cancer MDT before initiating.
Dosing
- 150 mg orally once daily.
- With or without food.
- Continue until disease progression or unacceptable toxicity.
- Treatment 'holidays' (intermittent dosing) may improve tolerability with limited loss of efficacy.
Response
Pivotal ERIVANCE trial: objective response rate ~43% laBCC, ~30% mBCC; median duration of response 7.6 months (mBCC), 9.5 months (laBCC). Real-world responses in laBCC may be higher.
Adverse events
- Muscle spasms (~70%) — usually mild but may limit adherence.
- Alopecia (~60%) — diffuse, recovers slowly after stopping.
- Dysgeusia / ageusia (~55%) — taste loss, food aversion.
- Weight loss (~45%).
- Fatigue, nausea, decreased appetite.
- Amenorrhoea in pre-menopausal women (often persistent).
- Hyponatraemia; raised CK.
- Second primary cSCC — emerging concern; counsel and monitor.
Vismodegib is a potent teratogen. Pregnancy must be excluded before starting. Female patients of childbearing potential must use the UK Pregnancy Prevention Programme: two contraception methods during treatment and for 24 months after the last dose; do not breastfeed or donate blood during that period. Counsel male patients about drug in semen — condom use during treatment and for 2 months after the last dose (UK SmPC; the FDA label specifies 3 months), and no semen donation during that period.
Practical considerations
- Baseline pregnancy test in pre-menopausal women; LFT; serum sodium; CK.
- Discuss likely impact on quality of life — alopecia and dysgeusia commonly drive discontinuation.
- Treatment 'holidays' (e.g. 8 weeks on, 4–8 weeks off) studied (MIKIE) — preserve efficacy with better tolerability.
- Sonidegib (Odomzo) is an alternative SMO inhibitor — EMA-licensed for advanced BCC, with similar efficacy and tolerability profile. There is no current positive UK NICE appraisal for sonidegib.
References
- Sekulic A et al. Vismodegib in advanced basal-cell carcinoma (ERIVANCE). N Engl J Med; 2012.
- NICE. Vismodegib for treating basal cell carcinoma (TA489). 2017 — not recommended for routine NHS use; any UK use via individual funding request or specialist commissioning.
- Dréno B et al. Vismodegib intermittent dosing (MIKIE). Lancet Oncol; 2017.
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