Vismodegib Continues to Prove BCC Effectiveness

Study 2: Basal Cell Nevus Syndrome

In a second randomized, double-blind, placebo-controlled trial of 41 patients with basal cell nevus syndrome, Dr. Jean Y. Tang and colleagues found that vismodegib reduced BCC tumors and blocked the development of new BCCs.

Basal cell nevus syndrome is rare, but it causes hundreds or thousands of carcinomas in each patient. There is no therapy, and often patients have to undergo multiple surgeries to remove the tumors.

Patients with the condition have one defective copy of the tumor suppressor gene (PTCH1), which inhibits the hedgehog signaling pathway, noted Dr. Tang of Stanford University (Calif.), and her colleagues.

The study enrolled patients from Sept. 2009 through Jan. 2011, but in Dec. 2010 the data safety and monitoring board decided to end the placebo treatment because the results so highly favored vismodegib. Patients were randomized to placebo or 150 mg daily of the drug for a planned 18 months.

The primary end point was the comparative rate of appearance of new BCCs that were eligible for surgery. Patients were followed for a mean of 8 months. Those who took vismodegib had a much lower rate of surgically eligible disease: 2 vs. 29 cases for placebo. Existing carcinomas shrunk by 65% in vismodegib-treated patients, compared with only 11% for placebo patients. Vismodegib patients also had fewer surgeries than patients receiving placebo: 0.31 per patient compared with 4.4 per patient, respectively.

At 1 month, there was a 90% reduction in hedgehog target-gene expression. There was no residual carcinoma in 83% of the biopsy samples taken from sites where the disease had been judged to be clinically regressed (N. Engl. J. Med. 2012;366:2180-8).

Fifty-four percent of study patients discontinued treatment because of adverse events. Patients treated with vismodegib were more likely to have grade 1 or 2 dysgeusia, muscle cramps, hair loss, and weight loss. They also had more grade 3 or 4 adverse events. The authors said that these side effects were similar to those reported in phase 1 and 2 trials of vismodegib, and also in other studies of therapies that inhibit the hedgehog pathway.

The authors concluded that vismodegib reduces tumor burden and blocks new tumor growth, but whether some of the clinically regressed tumors still harbor residual tumor cells cannot be ruled out – which could explain why there is tumor regrowth after therapy is stopped.

However, the "findings confirm the essential role of the hedgehog pathway in basal cell carcinomas," they wrote.

The trial was funded by Genentech and by grants from the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Cancer Institute, the Swim Across America Foundation, and the Michael J. Rainen Family Foundation. Dr. Tang reported receiving consulting fees from Genentech. Several coauthors of the study reported receiving grants or fees from Genentech.