On 30 January 2012 the FDA approved the novel small-molecule drug vismodegib, marketed by Roche as Erivedge^®, for the treatment of adults with metastatic or recurring basal cell carcinoma (BCC) [1].

Basal cell carcinoma is the commonest type of skin cancer. It is, in fact, an extremely common condition, affecting up to 30% of Caucasians at some point during their lifetime and in most cases it is very easily cured by surgical excision alone.

It does recur occasionally, however, and when it does it is much harder to treat. Locally advanced and metastatic BCC are also rare, but these conditions can cause severe deformity of the affected body region, disability, or even death.

Vismodegib is the first drug to be approved for treating BCC that has recurred after surgery or that has advanced locally or metastasized.

The approval was given following a single Phase II trial, ERIVANCE BCC (SHH4476g). Results from this single-arm trial were presented at the seventh European Association of Dermato-Oncology meeting, held in 2011 in Nantes, France.

The study enrolled 96 patients with a pathologically confirmed diagnosis of advanced BCC, 63 with locally advanced and 33 with metastatic disease. All patients received the same daily dose of 150mg of vismodegib. The primary endpoint of the trial was objective response rate (ORR). 

In this trial, the objective response rate was found to be 30.3% (95% CI: 15.6, 48.2) and 42.9% (95% CI: 30.5, 56.0) respectively in patients with metastatic and locally advanced disease, and the median response time was 7.6 months for both groups of patients.

Thirteen (20.6%) patients with locally advanced disease had complete responses; all responses in patients with metastatic disease were partial. There were relatively few moderate or severe adverse reactions, with Grade 3 muscle spasms, fatigue, weight loss and decreased appetite each being reported by more than 10% of patients.

Vismodegib inhibits the action of the Hedgehog (HH) signalling pathway, which is a regulator of embryonic development that is involved in establishing the body plan of the organism [2]. It has also been implicated in the regulation of stem cells in adult tissues. Several cancers, including BCC and a severe paediatric tumour, medulloblastoma, have been associated with aberrant signaling in this pathway.

This drug is an antagonist at a G-protein coupled receptor-like protein in this pathway known as Smoothened (SMO): it competes with a naturally occurring antagonist, cyclopamine. As the only known function of this protein is to regulate signaling in the Hedgehog pathway, antagonists at this receptor other specific for this pathway, and there are several other cyclopamine-like molecules in development as anti-cancer drugs. Vismodegib, however, is the first such drug to receive regulatory approval.

The Hedgehog pathway was co-discovered in the 1990s by scientists at what is now Cancer Research UK (CRUK). Speaking after vismodegib was granted approval, Dr Keith Blundy, CEO of Cancer Research Technology, the technology development and commercialization arm of CRUK, said “We're delighted that Vismodegib has been approved by the FDA… this is a great example of how early basic research funded by the charity can be translated into patient benefit.”

References

[1] Approved Drugs: Vismodegib  http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289571.htm

[2] Leading Hedgehog inhibitor submitted for approval as skin cancer drug. Nature Reviews Drug Discovery 10, 502-3. doi: 10.1038/nrd3594