Novel Hedgehog Pathway Inhibitor Combats Basal Cell Nevus Syndrome

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin’s syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.