'Greatest Advance in Therapy' for Basal Cell Carcinoma

Roxanne Nelson

June 15, 2012

June 15, 2012 — Vismodegib (Erivedge) "is the greatest advance in therapy yet" for the treatment of basal cell carcinoma (BCC), according to an editorial published in the June 7 issue of the New England Journal of Medicine.

"It is a landmark day for patients with basal cell carcinoma and all those involved in their care," writes John T. Lear, MD, from the University of Manchester, United Kingdom. His editorial accompanies 2 studies reporting the "remarkable effects of vismodegib."

One of the studies provides final results from a clinical trial of patients with metastatic and locally advanced BCC. These results led to the approval of vismodegib earlier this year.

Earlier results from this study, showing a "substantial benefit in BCC," were presented at the 2011 European Multidisciplinary Cancer Congress, as reported at that time by Medscape Medical News.

The other study showed that vismodegib decreases the incidence of new BCCs and reduces the size of existing BCCs, compared with placebo, in patients with the basal cell nevus syndrome, a rare heritable condition caused by a germ-line deletion of one copy of the PTCH1 gene. The syndrome can lead to the development of hundreds to thousands of BCCs in affected people.

"This therapy is tailor-made for patients with the basal cell nevus syndrome," Dr. Lear writes.

Advanced BCC

The study of patients with advanced BCC, which led to the drug's approval, was led by Aleksandar Sekulic, MD, PhD, assistant professor of dermatology at the Mayo Clinic in Rochester, Minnesota. It involved patients with metastatic BCC and those with locally advanced inoperable BCC for whom surgery was inappropriate. All patients were enrolled over a period of 13 months at 31 sites in Australia, Europe, and the United States, and all received oral vismodegib 150 mg daily.

Dr. Sekulic and colleagues report that the study met its primary end point of independently assessed objective response in both groups.

In the 33 patients with metastatic BCC, the response rate with vismodegib was 30% (P = .001); in the 63 patients with locally advanced BCC, the response rate was 43% (P < .001). Complete responses were seen in 13 patients.

In patients with metastatic BCC, at the data cutoff point, the median duration of objective response assessed by independent review was 7.6 months and assessed by site investigators was 12.9 months. Median progression-free survival was 9.5 months and 9.2 months, respectively.

In patients with locally advanced BCC, at the data-cutoff point, disease had not progressed in 10 of 13 patients. Median duration of objective response assessed by independent review was 7.6 months and assessed by site investigators was 7.6 months, and median progression-free survival was 9.5 months and 11.3 months, respectively.

Data for overall survival in the 2 groups are not yet mature.

Dr. Sekulic and colleagues note that adverse events that occurred in more than 30% of patients included muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Serious adverse events were reported in 25% of patients, and 7 deaths were related to adverse events.

Basal Cell Nevus Syndrome

In the second study, Jean Y. Tang, MD, PhD, assistant professor of dermatology at Stanford University in California, and colleagues conducted a randomized, double-blind, placebo-controlled trial comparing vismodegib with placebo in 41 patients with the basal cell nevus syndrome at 3 centers from September 2009 to January 2011. The primary end point was reduction in the incidence of new surgically eligible BCCs after 3 months; secondary end points included reduction in the size of existing lesions.

The researchers found that after a mean of 8 months, the per patient rate of new BCCs was lower in the vismodegib group than in the placebo group (2 vs 29 cases per year; P < .001). The size of the lesions, defined as the percentage change from baseline in the sum of the longest diameter of existing clinically significant BCCs, was also smaller (–65% vs –11%; P = .003).

At 1 month, vismodegib had decreased hedgehog target-gene expression in BCC by 90% (P < .001). It also reduced tumor cell proliferation, but did not affect apoptosis. Residual BCC was not detectable in 83% of biopsy samples obtained from sites of clinically regressed lesions.

Patients in the vismodegib group underwent fewer surgeries as part of standard care than those in the placebo group (mean number of surgeries per patient, 0.31 vs 4.4; median, 0.0 vs 1.0; P < .001). All tumors responded to vismodegib, and some patients achieved nearly complete clinical remissions. In addition, palmar and plantar pits, which are pathognomonic signs of this syndrome, disappeared in the vismodegib group, often within the first month.

However, the rate of adverse events was high. In the vismodegib group, 54% of patients discontinued treatment, and only 1 of 5 eligible patients was able to continue treatment for 18 months.

Adverse Effects Are a Problem

In his editorial, Dr. Lear notes that the adverse effects of vismodegib are considerable and frequent; in both studies, they resulted in high rates of drug discontinuation.

"These rates will probably be even higher in clinical practice," he writes. "Taste loss, hair loss, and muscle cramps are class effects and are unlikely to be attenuated by alteration of the compound structure."

He points out that there is also the "question of whether inhibition of the hedgehog pathway truly clears basal cell carcinomas or whether it leaves clones of resistant cells with the potential for recurrence or rebound."

Follow-up studies will be needed to address this issue, but currently, there does not appear to be the treatment resistance seen in other hedgehog-pathway-driven tumors. However, it might be too early to make such an assessment, Dr. Lear explains. "A number of other hedgehog-pathway inhibitors are under investigation, and it will be interesting to see what differences emerge."

Dr. Lear notes that the diagnosis of locally advanced basal cell carcinoma is subjective. "There is a need to define this disorder clinically and epidemiologically," he concludes. "Health economic analyses will be crucial for the adoption and use of vismodegib and similar agents around the world."

Both studies were funded by Genentech. Several of the authors report financial relationships, as detailed in the papers.

N Engl J Med. 2012;366: 2171-2179, 2180-2188, 2225-2226. Abstract, Abstract, Editorial

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