Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma

Background: Vismodegib is an oral inhibitor of the Hedgehog pathway approved by the US Food and Drug Administration. It is the first systemic treatment for patients with locally advanced or metastatic basal cell carcinoma that is not amenable to surgery and radiation. This is the first drug to use the Hedgehog pathway to inhibit the proliferation of tumors and is also implicated in the development of other cancers such as medulloblastoma.

Objective: The goal of this review was to summarize the development, pharmacology, efficacy, and safety of vismodegib.

Methods: Relevant English-language literature was identified and then evaluated based on results from database searches of MEDLINE and EMBASE from 1975 to June 19, 2012. The terms searched included, but were not limited to, vismodegib, Erivedge, GDC-0449, basal cell carcinoma, and 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide. Additional literature was identified by assessing the reference lists of previously identified articles and through abstracts presented by the American Society of Clinical Oncology.

Results: A total of 70 full text citations were identified although two national conference proceedings were then excluded. An additional 10 published abstracts were also identified. A Phase II, nonrandomized, multicenter, international study demonstrated a 30.3% objective response rate in metastatic basal cell carcinoma and a 42.9% objective response rate in locally advanced basal cell carcinoma. The adverse effect profile for vismodegib is similar to other identified Hedgehog pathway inhibitors; muscle cramps (71.7%), alopecia (63.8%), and dysgeusia (55.1%) were the most common adverse effects seen in trials. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with basal cell carcinoma concluded that vismodegib was significantly better than placebo at reducing new basal cell carcinoma lesions (P < 0.001) and at decreasing the sum of the longest diameter of existing lesions (P = 0.003).

Conclusions: For patients with unresectable basal cell carcinoma or where resection would be cosmetically disadvantageous, vismodegib is an effective therapy with good response rates. At this time, the data are too limited to determine overall survival. The Hedgehog pathway is a newly identified area in which mutations or dysregulation can occur, leading to the development and progression of tumors. Studies continue to look at other cancers with involvement of the Hedgehog pathway.