September 29, 2011 (Stockholm, Sweden) — The investigational drug vismodegib, which has a novel mechanism of action (inhibiting the hedgehog signaling pathway), has shown "substantial clinical benefit" in advanced basal cell carcinoma, in both metastatic and locally advanced settings.
This finding comes from a pivotal trial of the product in 104 patients, presented here at the 2011 European Multidisciplinary Cancer Congress. The results were presented by Luc Dirix, MD, from the Iridium Kankernetwerk, Antwerp, Belgium, from a paper selected as a best abstract for the presidential session.
Vismodegib is "a potential new therapy" for advanced basal cell carcinoma, he told the meeting attendees. It is under development by Genentech/Roche, which has recently filed an approval application with the US Food and Drug Administration for its use in the treatment of inoperable advanced basal cell carcinoma.
The results from the pivotal trial were "totally convincing" and there were some "very spectacular responses" said Caroline Robert, MD, PhD, from the Institut Gustave Roussy in Paris, France, who acted as discussant for the paper.
"Vismodegib is a breakthrough for the treatment of advanced basal cell carcinoma," she said, but cautioned that "long-term tolerance is an issue."
This novel drug is the first in the class of hedgehog pathway inhibitors. This pathway is disrupted in about 90% of basal cell carcinomas; it is also affected in several other cancers, including medulloblastoma.
Advanced Cases Not Operable
Basal cell carcinoma is the most commonly diagnosed human cancer, with more than 2 million cases each year in the United States, Dr. Dirix noted.
Most cases are treated with surgery, he explained. However, a small proportion of patients (less than 5%) progress to locally advanced or even metastatic disease, for which there is currently no standard of care.
In a phase 1 study of 33 patients with advanced basal cell carcinoma, vismodegib showed a 55% response rate and was generally well tolerated (N Engl J Med. 2009;361:1164-1172). The results generated considerable excitement among scientists, and were heralded as a new era in the treatment of basal cell carcinoma.
Those results led to the pivotal phase 2 study conducted by Dr. Dirix's team. Patients recruited to this study had histologically confirmed basal cell carcinoma that was inoperable, or were patients for whom surgery would be significantly disfiguring, he explained. All patients had either locally advanced (n = 63) or metastatic (n = 63) disease, and all received treatment with vismodegib 150 mg orally until progression or until withdrawal from the study.
"Nearly all patients had some tumor shrinkage," Dr. Dirix reported.
Of the patients with locally advanced disease, 43% responded, and "many had huge responses with massive decreases in tumor size," he said. One patient had no evaluable basal cell carcinoma after treatment, he noted.
Patients with locally advanced disease, assessed by independent review, had an overall response rate of 43% (95% confidence interval [CI], 31% to 56%; P < .0001), and patients with metastatic disease had an overall response rate of 30% (95% CI, 16% to 48%; P = .0011).
Median time to progression was 9.5 months for both groups of patients, Dr. Dirix noted.
Adverse events that were reported in more than 30% of patients included muscle spasms, alopecia, taste disturbance, weight loss, and fatigue. Serious adverse events were reported in 26 patients (25%); in 4 patients the serious adverse event was considered to be related to the vismodegib. Fatal adverse events were reported in 7 patients (7%), but none were considered to be related to the drug.
In her discussion of the study, Dr. Robert drew attention to these tolerability findings. She noted that in a another study of vismodegib, conducted in 41 patients with Gorlin syndrome, about 30% stopped taking the drug because of adverse events, and most patients could not tolerate the drug for more than 18 months.
Dr. Robert speculated that there might be a use for vismodegib in the neoadjuvant treatment of advanced basal cell cancer, for example with patients taking it for 3 months or so to shrink their tumors and then undergoing surgery. "We need to explore other modalities," she said, and "surgery must always remain in the algorithm."
Dr. Robert also provided interesting insight into how the drug was developed. Cyclopamine, a chemical extracted from the corn lily, was found to be an inhibitor of the hedgehog pathway. Attention was drawn to this plant after it was noticed that sheep that fed on the flowers while they were pregnant gave birth to deformed offspring, with only 1 eye and brain malformations.
The trial was funded by Genentech/Roche, the companies that are developing vismodegib.
2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 1BA. Presented September 24, 2011.
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Cite this: Vismodegib: 'Substantial Benefit' in Basal Cell Carcinoma - Medscape - Sep 29, 2011.