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Hedgehog Blocker Works in Basal Cell Cancers


By Kristina Fiore, Staff Writer, MedPage TodayPublished: June 06, 2012Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.


Vismodegib (Erivedge), which blocks the hedgehog signaling pathway that’s involved in basal cell carcinoma, improves control of tumor growth in advanced disease and prevents the appearance of new lesions in severe forms of the cancer, according to two trials.

In one phase II study — the results of which factored into the drug’s January 2012 approval — 30% of patients with metastatic disease and 43% of those with locally advanced disease responded to treatment (P=0.001 and P<0.001, respectively), according to Aleksandar Sekulic, MD, of the Mayo Clinic in Scottsdale, Ariz., and colleagues.

And in a phase II trial, patients with basal cell nevus (Gorlin) syndrome had significantly fewer new lesions with the drug than with placebo (two versus 29 cases per group per year, P<0.001), according to Ervin Epstein Jr., MD, of Children’s Hospital of Oakland Research Institute in California, and colleagues.

However, more than half of patients in that trial eventually discontinued therapy because of side effects such as loss of taste, muscle cramps, hair loss, and weight loss.

Both studies were published in the June 7 issue of the New England Journal of Medicine.

Basal cell carcinoma is the most common cancer in the U.S. and often involves genetic alteration of the hedgehog signaling pathway — one that plays a key role in early human development.

Vismodegib inhibits that pathway, which is overactive in these cancers, and was recently approved for use in patients with metastatic or locally advanced disease who aren’t candidates for radiation or surgery.

Researchers also were interested in investigating whether the drug could benefit patients with basal cell nevus syndrome, a more aggressive form of the disease in which patients can be afflicted with hundreds of basal cell carcinomas.

For their randomized controlled phase II trial, Epstein and colleagues assessed 41 patients with the condition at three centers between September 2009 and January 2011.

The primary endpoint was reduction in new basal cell carcinomas that were eligible for surgical resection after 3 months.

They found that the rate of these new lesions was significantly lower among patients on vismodegib compared with those on placebo (mean two versus 29 cases per group per year,P<0.001).

The reduction occurred early on, at one month, they reported.

They also found that lesion shrinkage was significantly better with the drug than with placebo (-65% versus -11% in terms of change from baseline in the sum of the longest diameter, P=0.003).

However, adverse events appeared to be a problem. Most patients on vismodegib routinely had grade 1 or 2 adverse events including loss of taste, muscle cramps, hair loss, and weight loss.

They also had significantly more grade 3 or 4 adverse events than those on placebo, the researchers said.

By the data cutoff point, 54% of drug-treated patients discontinued therapy because of these events. When the drug was stopped, the loss of taste and muscle cramps ceased within 1 month, and scalp and body hair started to regrow within 3 months, they noted, although most surgically eligible lesions regrew once the drug was stopped.

In the other trial, Sekulic and colleagues enrolled patients with locally advanced or metastatic basal cell carcinoma who weren’t candidates for surgery in a multicenter, international phase II study.

The majority of patients with metastatic disease had three or more target lesions, with the most frequent sites being the lung and lymph nodes.

All patients received 150 mg of oral vismodegib daily, and the primary endpoint was objective response rate.

Sekulic and colleagues found that among the 33 patients with metastatic disease, the response rate was 30% (95% CI 16 to 48, P=0.001), and in the 63 patients with locally advanced disease, the response rate was 43% (95% CI 31 to 56, P<0.001).

They saw a complete response in 13 patients with locally advanced disease (21%), and the median duration of response was 7.6 months in both cohorts.

Adverse events that occurred in more than 30% of patients included muscle spasms, hair loss, loss of taste, weight loss, and fatigue. Serious adverse events occurred in 25% of patients.

There also were seven deaths in the trial, though the researchers said the relationship between the study drug and deaths isn’t clear. The site investigator considered the deaths to be unrelated to vismodegib, they reported.

As of the data cutoff point, about half of patients had discontinued the study drug.

In an accompanying editorial, John Lear, MD, of Manchester University, called vismodegib the “greatest advance in therapy yet seen for this disease.”

Lear cautioned, however, that the side effects are “considerable and frequent, resulting in high rates of drug discontinuation, and these rates will probably be even higher in clinical practice. Taste loss, hair loss, and muscle cramps are class effects and are unlikely to be attenuated by alteration of the compound structure.”

He added that there’s also a question about whether inhibiting the hedgehog pathway truly clears basal cell carcinomas or if it leaves clones of resistant cells with the potential for recurrence or rebound.

Lear concluded that the therapy also may benefit patients with regular basal cell carcinoma, especially if an effective topical formulation, either cream or injectable, would be developed: “targeted therapy could be offered to many patients rather than restricted to the few who are severely affected.”

The studies were supported by Genentech. The Tang study also was supported by grants from the National Instiutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Cancer Institute, the Damon Runyon Cancer Research Foundation, the Swim Across America Foundation, and the Michael J. Rainen Family Foundation.

Tang and colleagues reported relationships with Genentech, Novartis, Curis, Infinity, and CHORI.

Sekulic and colleagues reported relationships with Genentech, Roche, Novartis, AstraZeneca, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, SOBI, Infinity, Syndax, OSI Pharmaceuticals, Aveo Pharmaceuticals, and Oncothyreon.

Lear reported relationships with Novartis.