American Melanoma Institute · 5 min read
How vismodegib and sonidegib switch off the pathway that drives basal cell carcinoma, who takes them, verified trial results, side effects, and what comes next.
Nearly all basal cell carcinomas are cured with a minor procedure. A small number grow so large or come back so many times that surgery and radiation can no longer fix them, and a very few spread to lymph nodes or distant organs. For these advanced cases, 2 pills target the exact molecular fault behind the cancer.
The hedgehog pathway is a chain of signals that tells cells when to grow. The pathway is busy in the embryo and falls mostly silent in adults.
A pair of proteins on the cell surface controls it. PTCH1 is the brake. SMO, short for smoothened, is the accelerator. In basal cell carcinoma, ultraviolet damage has usually knocked out PTCH1 or, less often, jammed SMO in the on position, and the growth signal fires nonstop. Around 95% of basal cell carcinomas show abnormal hedgehog signaling, according to the sonidegib trial's authors.
Vismodegib (brand name Erivedge) and sonidegib (Odomzo) both bind to SMO and shut it off. Each is a once-daily capsule.
The FDA approved vismodegib in 2012 for adults with metastatic basal cell carcinoma, and for locally advanced disease that has come back after surgery or in people who are not candidates for surgery or radiation. Sonidegib, approved in 2015, covers locally advanced disease that recurred after surgery or radiation, or in people who cannot have those treatments. Its approval does not extend to metastatic disease.
Locally advanced has no strict size definition. In practice it means a tumor where surgery would cost an eye, a nose, or an ear, or a tumor that keeps returning despite good treatment. A team of specialists usually makes the call together.
Vismodegib's approval rested on the ERIVANCE trial (Sekulic and colleagues, New England Journal of Medicine, 2012), which treated 104 patients. Independent reviewers found that tumors shrank substantially in 43% of patients with locally advanced disease and 30% of those with metastatic disease. The treating doctors' own assessments were higher, 60% and 45%. In the final 2017 update, responses in locally advanced disease lasted a median of about 26 months.
Sonidegib was tested in the BOLT trial (Migden and colleagues, Lancet Oncology, 2015), which randomized 230 patients to 200 mg or 800 mg a day. The lower dose worked as well with fewer side effects, and the FDA approved that dose. Central reviewers first recorded responses in 43% of patients with locally advanced disease and 15% of the small metastatic group. With longer follow-up, the current FDA label reports a 56% response rate in locally advanced disease.
Neither trial had a comparison group, and the 2 drugs have never been tested against each other. Tumors can develop resistance, and they often regrow after the drug is stopped.
Hedgehog signaling stays active in a few adult tissues: hair follicles, taste buds, and muscle cell membranes. The side effects follow from that, and nearly everyone gets some. In the vismodegib label, the most frequent were:
Sonidegib causes the same set and can also raise the blood level of creatine kinase, an enzyme released by stressed muscle, so doctors check that level before and during treatment.
Most of these effects are graded mild or moderate. They are also relentless. In a trial of vismodegib for basal cell nevus syndrome, 54% of those taking the drug stopped because of side effects. In BOLT, 22% of patients on the 200 mg dose quit for that reason.
Doctors manage this with planned treatment breaks. Taste and muscle symptoms fade within weeks to months of stopping.
Both drugs carry the FDA's strongest warning, a boxed warning, because blocking the hedgehog pathway in an embryo can cause death of the embryo or severe birth defects. Women who could become pregnant need effective contraception throughout treatment and afterward: for 24 months after the last dose of vismodegib and at least 20 months after sonidegib.
The drugs may be present in semen. Men should use condoms during treatment and for 3 months after vismodegib or at least 8 months after sonidegib. No one taking either drug should donate blood during treatment or for the same 24-month or 20-month window afterward.
People with basal cell nevus syndrome, also called Gorlin syndrome, are born with 1 faulty copy of PTCH1 and can develop hundreds of basal cell carcinomas in a lifetime. A randomized trial enrolled 41 such patients (Tang and colleagues, New England Journal of Medicine, 2012). Vismodegib cut the rate of new tumors needing surgery from 29 per patient per year on placebo to 2.
The tumors returned after people stopped. For this group the drug reduces the number of surgeries without curing the condition, and this use is off-label.
The next step is immunotherapy. Cemiplimab (Libtayo) is a PD-1 checkpoint inhibitor, a drug that releases a brake on immune cells so they can attack the tumor. The FDA has approved it for locally advanced or metastatic basal cell carcinoma in people previously treated with a hedgehog inhibitor or for whom a hedgehog inhibitor is not appropriate.
Cemiplimab is given through a vein, typically every 3 weeks. Fatigue, rash, diarrhea, and joint pain are the usual side effects, and less often the activated immune system inflames the lungs, bowel, liver, or kidneys.
