Vismodegib effective against basal cell nevus syndrome

Key Points

National report - The hedgehog inhibitor drug vismodegib (Erivedge, Genentech/Roche), approved in January to treat advanced and metastatic basal cell carcinoma, has demonstrated potent clinical activity when used in patients with basal cell nevus syndrome, according to a study published recently in the New England Journal of Medicine.

While most patients showed dramatic improvement, they also experienced significant but non-life-threatening side effects that make continuous long-term use uncommon. It appears that episodic use, possibly in combination with other interventions, will be tailored to individual patient's needs and tolerance of the drug.

Study details

The primary endpoint was the comparative rate of appearance of new basal cell carcinomas that were eligible for surgical resection, while secondary endpoints included a reduction in size of the existing lesions and side effects.

At the second interim analysis, in December 2010, the DSMB found statistically and clinically significant differences in responses and recommended that the placebo group be stopped and those patients offered vismodegib. That occurred in February 2011.

Analysis of the unblinded data revealed that patients saw no tumor progression while on vismodegib. And even if they had stopped taking the drug during the study period, patients in the vismodegib group saw far fewer new tumors than those on placebo (two versus 29).

At one month, vismodegib use had reduced the hedgehog target-gene expression by basal cell carcinoma (BCC) by 90 percent (P<0.001) and diminished tumor-cell proliferation. No residual basal cell carcinoma was detectable in 83 percent of biopsy samples taken from sites of clinically regressed basal cell carcinomas.

Adverse events

There were no hospitalizations attributed to the drug. The other piece of good news is that most side effects reversed within a month of discontinuing the drug.

"The dropout rate surprised me," says Jean Tang, M.D., Ph.D., the lead author of the study and an assistant professor of dermatology at Stanford University School of Medicine, Stanford, Calif. The study had planned for 20 percent over 18 months, but about half (54 percent) of the patients stopped taking the drug in a much shorter period of time.

Another surprise was how quickly they saw the anti-BCC effect of the drug, generally within a month or two of beginning treatment, Dr. Tang says. The two factors more than balanced out, so there was no question of the study being sufficiently powered to determine statistical significance, she explains.

Finally, there was a surprise in seeing no correlation between plasma levels of vismodegib and either response to therapy or side effects. "There must be different genes and metabolism involved," Dr. Tang says.