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The pills that shrink advanced basal cell carcinoma cause muscle cramps, loss of taste, hair loss and weight loss in almost everyone who takes them. None of that is dangerous, and most people stop anyway, because the drug has to be taken for years and it takes the pleasure out of eating and moving.
Vismodegib and sonidegib block smoothened, the receptor through which the hedgehog pathway signals. The pathway is not only a cancer driver: it runs hair follicles, taste buds and muscle, which is exactly where the side effects land. They are class effects, they are dose-related and they are not avoided by choosing the other drug.
STEVIE measured the size of the problem outside a pivotal trial, in 1,215 patients in 36 countries. Ninety-eight per cent had at least one treatment-emergent adverse event and 23.8 per cent had a serious one; the median treatment duration was 8.6 months and only 12 per cent were still taking the drug when the analysis was done. Response was good, at 68.5 per cent in locally advanced disease, so this is not a failure of efficacy. It is a drug people cannot live on.
Three responses to that have been tried. Intermittent dosing, tested in the MIKIE study, gives planned breaks and was studied with quality-of-life outcomes. Neoadjuvant use gives a short defined course with an operation at the end rather than open-ended treatment: VISMONEO downstaged the surgery in 80 per cent of 55 patients over a mean 6.0 months. Topical delivery puts the drug where the tumour is and not in the muscles: patidegib gel showed a signal in Gorlin syndrome in post hoc analyses of a seventeen-patient phase 2A study.
The second limit on the class is resistance. Acquired mutations in smoothened restore signalling downstream of the drug, and there is no approved next-in-class agent for them. The answer that reached the clinic came from outside the pathway altogether: cemiplimab, a PD-1 antibody, produced responses in 31 per cent of 84 patients whose disease had progressed on or could not tolerate a hedgehog inhibitor.
In England none of this is funded. NICE technology appraisal TA489 recommendation 1.1 does not recommend vismodegib for metastatic basal cell carcinoma or for locally advanced disease unsuitable for surgery or radiotherapy, on the grounds of uncertain evidence and a cost per quality-adjusted life year far above 30,000 pounds, and there is no NICE appraisal of sonidegib or of cemiplimab in this disease at all.
In plain words · The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
Showing the target this term concerns: Smoothened (hedgehog pathway).
Shares Patidegib, Hedgehog pathway inhibitors, Sonidegib, Smoothened (hedgehog pathway).
Shares Sonidegib, BOLT, ERIVANCE BCC, Smoothened (hedgehog pathway).
Shares Hedgehog pathway inhibitors, Vismodegib, Locally advanced and metastatic basal cell carcinoma, Basal cell carcinoma.
Shares Sonidegib, BOLT, Locally advanced and metastatic basal cell carcinoma.
Shares ERIVANCE BCC, Vismodegib, Locally advanced and metastatic basal cell carcinoma.
Shares Cemiplimab in basal cell carcinoma after a hedgehog inhibitor, Locally advanced and metastatic basal cell carcinoma, Cemiplimab.
Shares Cemiplimab, Basal cell carcinoma, Skin cancer (all types).
Shares VISMONEO (vismodegib before surgery for locally advanced basal cell carcinoma), Locally advanced and metastatic basal cell carcinoma, Basal cell carcinoma, Skin cancer (all types).