For Some Skin Cancers, Targeted Drug Hits the Mark

Adapted from the NCI Cancer Bulletin.

In January, the Food and Drug Administration approved a drug called vismodegib (Erivedge™) for treating advanced cases of basal cell carcinoma (BCC). The vast majority of BCCs, the most common form of skin cancer, can be treated surgically, but patients with locally advanced or metastatic disease have had no effective treatments until this year.

Final results from the trial that led to the approval of vismodegib appeared in the New England Journal of Medicine on June 7, 2012. A companion report describes how vismodegib, which is taken as a pill, prevented and shrank tumors in people with basal cell nevus syndrome (BCNS), an inherited condition that can cause a person to develop hundreds to thousands of BCCs.

“It is a landmark day for patients with basal cell carcinoma and all those involved in their care—the greatest advance in therapy yet seen for this disease,” noted John T. Lear, M.B., Ch.B., of University of Manchester in an accompanying editorial. But continuous administration of the drug can cause “considerable and frequent” side effects, including muscle cramps, hair loss, and loss of the sense of taste. 

These side effects led some patients to stop taking the drug, he noted. One-quarter of the patients experienced serious adverse events, and seven died. "The relationship between the study drug and the deaths is unknown," the researchers wrote.

Modified dosing schedules may limit the side effects and are being investigated, noted Aleksandar Sekulic, M.D., Ph.D., of the Mayo Clinic, who led the BCC study. In the phase II trial, 30 percent of patients with metastatic disease had a partial response, and 43 percent of patients with locally advanced disease had a complete or partial response. The study included 104 patients.

The BCNS study was a randomized trial involving 41 patients. Patients who received vismodegib developed, on average, two new BCCs that warranted surgery per year, compared with 29 new BCCs among those who received a placebo. However, more than half of the patients taking vismodegib discontinued treatment because of side effects. Once patients stopped taking the drug, tumors began to slowly reappear.

“We still feel that this medicine is a life-changing therapy for these patients,” said Jean Tang, M.D., Ph.D., of Stanford University, the first author of the study. “But patients cannot take the drug every day.” Her team has initiated a second trial to investigate the best way to give the drug.

The drug is designed to block signals that drive the growth of cancer cells though the Hedgehog signaling pathway. This pathway is silent in adult tissues, except in certain parts of the body, such as hair follicles. By shutting down the pathway in normal cells, the drug may cause hair loss and other side effects.

Although unpleasant, the side effects are an indication that the drug is hitting its target, noted Dr. Sekulic. These studies are “an important step forward,” he continued, adding that “the vast majority of BCCs can be prevented with good sun protection.”