Phase II studies show that vismodegib induces BCC regression and blocks new lesion growth.

  • Major finding: Phase II studies show that vismodegib induces BCC regression and blocks new lesion growth.

  • Mechanism: Vismodegib is a small-molecule Smoothened inhibitor that blocks Hedgehog pathway activation.

  • Impact: Vismodegib has been approved by the FDA for treatment of locally advanced and metastatic BCC.

The vast majority of basal-cell carcinomas (BCC), the most common human cancer, harbor genetic alterations that cause Hedgehog pathway upregulation. Most BCCs are treated surgically, but no effective therapy exists for metastatic or locally advanced BCC. Two phase II trials evaluated the safety and efficacy of vismodegib, an oral small-molecule inhibitor of Smoothened (a Hedgehog pathway activator). In the nonrandomized study by Sekulic and colleagues, 33 patients with metastatic BCC and 63 patients with inoperable locally advanced BCC took vismodegib daily. Strikingly, the majority of patients had visible tumor shrinkage with improved appearance. Decreases in tumor burden of 30% or more were observed in 30% of patients with metastatic BCC and 43% of patients with locally advanced BCC, 13 of whom had complete responses, and the median duration of response was 7.6 months. Tang and colleagues conducted a randomized, double-blind, placebo-controlled study of vismodegib in 41 patients with basal-cell nevus syndrome, a BCC predisposition syndrome in which the discovery of germline mutations in the Hedgehog pathway inhibitor PTCH1 provided the original evidence of overactive Hedgehog signaling in BCC. No tumors progressed on vismodegib, and compared with the placebo, vismodegib significantly reduced the size of existing BCCs (–65% vs. –11%) as well as the per-patient rate of new lesions (2 vs. 25 per year). Notably, 1 month of vismodegib treatment reduced expression of the Hedgehog target gene GLI1 by 90% in BCC biopsy specimens. In both trials, vismodegib frequently caused adverse effects such as hair loss, muscle cramps, taste disturbances, and weight loss that often led to drug discontinuation. However, these results established the efficacy of targeting the Hedgehog pathway in BCC and led to FDA approval of vismodegib for patients with locally advanced and metastatic BCC.

Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171–9.

Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the Hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012;366:2180–8.

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