The FDA approved sonidegib, an inhibitor of Hedgehog pathway signaling, to treat advanced basal cell carcinoma. It is the second such drug in a new class of targeted therapies.

The FDA has approved a second targeted treatment for locally advanced basal cell carcinoma (BCC). Sonidegib (Odomzo; Novartis) inhibits a key step in the Hedgehog pathway, a developmental regulatory cascade that is aberrantly activated in the majority of BCCs.

BCC is the most common form of skin cancer, accounting for 80% of skin cancers in the United States. Most cases can be cured with surgery, radiation, or topical medications, but until recently there was no effective treatment for the small number (1%–10%) of inoperable, recurrent, and metastatic tumors. That changed in 2012 with the approval of vismodegib (Erivedge; Genentech), an inhibitor of the smoothened (SMO) protein, a component of the Hedgehog pathway.

The FDA approved the SMO inhibitor sonidegib for basal cell carcinoma (above) in July. SMO is a component of the Hedgehog pathway.

The FDA approved the SMO inhibitor sonidegib for basal cell carcinoma (above) in July. SMO is a component of the Hedgehog pathway.

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The FDA approved sonidegib, another SMO inhibitor, based on results from the phase II BOLT study, which compared two doses (200 mg and 800 mg per day, given orally) in 194 patients with locally advanced BCC who were ineligible for surgery or radiation. Sonidegib showed durable antitumor activity, with 58% of the patients given the 200 mg dose achieving an objective response. Most side effects were mild to moderate, including muscle spasms, loss of sense of taste, and alopecia. Severe side effects included elevated creatine kinase levels and breakdown of muscle tissue. Because there was no evidence of better tumor response in the patients receiving the 800 mg dose of sonidegib, and adverse events were more common, the FDA approved the 200 mg dose.

The clinical activity and side effect profile of sonidegib appear similar to vismodegib's. Due to the importance of the Hedgehog pathway in fetal development, both drugs carry a black box warning about significant fetal toxicity.

With the approval of sonidegib, “we have two drugs that are very effective,” says William Sharfman, MD, director of cutaneous oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. “The challenge now is to figure out which patients with locally advanced disease can best benefit from the drug,” he says.

Sharfman notes that the drugs might be useful to shrink tumors before disfiguring surgery or delay the need for surgery, and studies of these neoadjuvant applications are under way.

The downfall of many molecularly targeted therapies is the development of resistance. Clinical experience suggests that about 20% of patients taking vismodegib develop resistance within a year, mainly through acquired mutations in SMO. Whether sonidegib will perform better remains unknown, says Jean Y. Tang, MD, PhD, a dermatologist and physician-scientist at California's Stanford University. Preliminary experience with the drugs suggests that cross-resistance does occur, says Tang.

Studies of sonidegib and other SMO inhibitors are also under way in medulloblastoma, another cancer caused by SMO mutations, as well as other tumors with Hedgehog pathway activation. “The hope is that this pathway or target is relevant for other cancers and that one can expand the treatment options for other deadly cancers,” says Tang.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.