Vismodegib Continues to Prove BCC Effectiveness

Two small, early-phase studies found that vismodegib is effective for the treatment of basal cell nevus syndrome and advanced basal cell carcinoma, according to results published June 6 in the New England Journal of Medicine.

Basal cell malignancies are among the most common nonmelanoma skin cancers in the United States, accounting for at least 80% of the 2.1 million cases. It is a highly disfiguring cancer but is only sometimes life threatening. Almost all basal cell carcinomas (BCCs) are caused by alterations in the hedgehog signaling pathway.

Vismodegib (Erivedge) was approved by the Food and Drug Administration in January for treating locally advanced and metastatic BCC. Vismodegib (manufactured by Genentech) is a small molecule inhibitor that steps in to repair the hedgehog pathway.

Courtesy of The New England Journal of Medicine, copyright 2012

Study 1: Locally Advanced and Metastatic BCC

In the first study, conducted before vismodegib received FDA approval for locally advanced and metastatic BCC, Dr. Aleksandar Sekulic and colleagues conducted a phase II, nonrandomized, two-cohort trial at multiple sites around the United States and overseas. Vismodegib was given to 33 patients with metastatic BCC and 63 patients with locally advanced disease. Both cohorts had inoperable disease or were not eligible for surgery.

All the patients were treated with 150 mg of oral vismodegib daily. The median age of patients was 62 years and all were white, noted Dr. Sekulic of the Mayo Clinic in Scottsdale, Ariz.

The patients were treated with vismodegib until disease progression, until side effects became intolerable, or until end of study. Patients could stop the drug for up to a month if side effects were intolerable.

There was no standard end point for measuring response in locally advanced BCC when the study was designed. The definition used was a decrease of 30% or more of the externally visible or radiographic dimension or complete resolution of ulceration. Progressive disease was an increase of 20% or more in the externally visible or radiographic dimension, new ulceration, or a new lesion.

The response rate for the metastatic group treated with vismodegib was 30%. All of the responses were partial, defined as an absence of residual BCC in a biopsy specimen. In locally advanced disease, the response rate was 43%. Thirteen of the 63 patients had a complete response. The median duration of response was 7.6 months for metastatic and locally advanced BCC patients (N. Engl. J. Med. 2012;366:2171-9).

Half of the patients stopped the drug early, with 18% of metastatic patients discontinuing because of disease progression. Twenty-five percent of locally advanced patients decided on their own to stop therapy, for unknown reasons, according to the investigators. Adverse events – primarily muscle spasms, weight loss, fatigue, and loss of appetite – took a toll on patients. A quarter reported serious adverse events.

Seven patients died, but the relation to vismodegib is not clear at this point. "The deaths were considered by the site investigator to be unrelated to vismodegib," the investigators wrote.

The locally advanced and metastatic BCC trial was funded by Genentech and was jointly designed by Genetech and Dr. Sekulic. A majority of his colleagues reported being employees and/or receiving grants or financial support from the company.

In an interview, Dr. Ali Hendi, assistant clinical professor of dermatology at Georgetown University Medical Center, Washington, said that he felt the investigators in the study were overly subjective in defining locally advanced tumors. "These are tumors that are aggressive, but that does not make them inoperable in the right hands," said Dr. Hendi, who is also a Mohs surgeon.

He also noted the slim complete response rate, which, when coupled with the toxicity and the high cost of the therapy – which might run as much as $70,000 per treatment course – make it a less desirable therapy for many patients.

"For locally advanced [disease] I think the utility is limited if there is good surgical care available," he said. Vismodegib may be more useful for BCC nevus syndrome and for metastatic disease, where it may be the only therapy available, he added.

Dr. Hendi reported no conflicts.

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.

Two small, early-phase studies found that vismodegib is effective for the treatment of basal cell nevus syndrome and advanced basal cell carcinoma, according to results published June 6 in the New England Journal of Medicine.

Basal cell malignancies are among the most common nonmelanoma skin cancers in the United States, accounting for at least 80% of the 2.1 million cases. It is a highly disfiguring cancer but is only sometimes life threatening. Almost all basal cell carcinomas (BCCs) are caused by alterations in the hedgehog signaling pathway.

Vismodegib (Erivedge) was approved by the Food and Drug Administration in January for treating locally advanced and metastatic BCC. Vismodegib (manufactured by Genentech) is a small molecule inhibitor that steps in to repair the hedgehog pathway.

Courtesy of The New England Journal of Medicine, copyright 2012

Study 1: Locally Advanced and Metastatic BCC

In the first study, conducted before vismodegib received FDA approval for locally advanced and metastatic BCC, Dr. Aleksandar Sekulic and colleagues conducted a phase II, nonrandomized, two-cohort trial at multiple sites around the United States and overseas. Vismodegib was given to 33 patients with metastatic BCC and 63 patients with locally advanced disease. Both cohorts had inoperable disease or were not eligible for surgery.

All the patients were treated with 150 mg of oral vismodegib daily. The median age of patients was 62 years and all were white, noted Dr. Sekulic of the Mayo Clinic in Scottsdale, Ariz.

The patients were treated with vismodegib until disease progression, until side effects became intolerable, or until end of study. Patients could stop the drug for up to a month if side effects were intolerable.

There was no standard end point for measuring response in locally advanced BCC when the study was designed. The definition used was a decrease of 30% or more of the externally visible or radiographic dimension or complete resolution of ulceration. Progressive disease was an increase of 20% or more in the externally visible or radiographic dimension, new ulceration, or a new lesion.

The response rate for the metastatic group treated with vismodegib was 30%. All of the responses were partial, defined as an absence of residual BCC in a biopsy specimen. In locally advanced disease, the response rate was 43%. Thirteen of the 63 patients had a complete response. The median duration of response was 7.6 months for metastatic and locally advanced BCC patients (N. Engl. J. Med. 2012;366:2171-9).

Half of the patients stopped the drug early, with 18% of metastatic patients discontinuing because of disease progression. Twenty-five percent of locally advanced patients decided on their own to stop therapy, for unknown reasons, according to the investigators. Adverse events – primarily muscle spasms, weight loss, fatigue, and loss of appetite – took a toll on patients. A quarter reported serious adverse events.

Seven patients died, but the relation to vismodegib is not clear at this point. "The deaths were considered by the site investigator to be unrelated to vismodegib," the investigators wrote.

The locally advanced and metastatic BCC trial was funded by Genentech and was jointly designed by Genetech and Dr. Sekulic. A majority of his colleagues reported being employees and/or receiving grants or financial support from the company.

In an interview, Dr. Ali Hendi, assistant clinical professor of dermatology at Georgetown University Medical Center, Washington, said that he felt the investigators in the study were overly subjective in defining locally advanced tumors. "These are tumors that are aggressive, but that does not make them inoperable in the right hands," said Dr. Hendi, who is also a Mohs surgeon.

He also noted the slim complete response rate, which, when coupled with the toxicity and the high cost of the therapy – which might run as much as $70,000 per treatment course – make it a less desirable therapy for many patients.

"For locally advanced [disease] I think the utility is limited if there is good surgical care available," he said. Vismodegib may be more useful for BCC nevus syndrome and for metastatic disease, where it may be the only therapy available, he added.

Dr. Hendi reported no conflicts.

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.

Two small, early-phase studies found that vismodegib is effective for the treatment of basal cell nevus syndrome and advanced basal cell carcinoma, according to results published June 6 in the New England Journal of Medicine.

Basal cell malignancies are among the most common nonmelanoma skin cancers in the United States, accounting for at least 80% of the 2.1 million cases. It is a highly disfiguring cancer but is only sometimes life threatening. Almost all basal cell carcinomas (BCCs) are caused by alterations in the hedgehog signaling pathway.

Vismodegib (Erivedge) was approved by the Food and Drug Administration in January for treating locally advanced and metastatic BCC. Vismodegib (manufactured by Genentech) is a small molecule inhibitor that steps in to repair the hedgehog pathway.

Courtesy of The New England Journal of Medicine, copyright 2012

Study 1: Locally Advanced and Metastatic BCC

In the first study, conducted before vismodegib received FDA approval for locally advanced and metastatic BCC, Dr. Aleksandar Sekulic and colleagues conducted a phase II, nonrandomized, two-cohort trial at multiple sites around the United States and overseas. Vismodegib was given to 33 patients with metastatic BCC and 63 patients with locally advanced disease. Both cohorts had inoperable disease or were not eligible for surgery.

All the patients were treated with 150 mg of oral vismodegib daily. The median age of patients was 62 years and all were white, noted Dr. Sekulic of the Mayo Clinic in Scottsdale, Ariz.

The patients were treated with vismodegib until disease progression, until side effects became intolerable, or until end of study. Patients could stop the drug for up to a month if side effects were intolerable.

There was no standard end point for measuring response in locally advanced BCC when the study was designed. The definition used was a decrease of 30% or more of the externally visible or radiographic dimension or complete resolution of ulceration. Progressive disease was an increase of 20% or more in the externally visible or radiographic dimension, new ulceration, or a new lesion.

The response rate for the metastatic group treated with vismodegib was 30%. All of the responses were partial, defined as an absence of residual BCC in a biopsy specimen. In locally advanced disease, the response rate was 43%. Thirteen of the 63 patients had a complete response. The median duration of response was 7.6 months for metastatic and locally advanced BCC patients (N. Engl. J. Med. 2012;366:2171-9).

Half of the patients stopped the drug early, with 18% of metastatic patients discontinuing because of disease progression. Twenty-five percent of locally advanced patients decided on their own to stop therapy, for unknown reasons, according to the investigators. Adverse events – primarily muscle spasms, weight loss, fatigue, and loss of appetite – took a toll on patients. A quarter reported serious adverse events.

Seven patients died, but the relation to vismodegib is not clear at this point. "The deaths were considered by the site investigator to be unrelated to vismodegib," the investigators wrote.

The locally advanced and metastatic BCC trial was funded by Genentech and was jointly designed by Genetech and Dr. Sekulic. A majority of his colleagues reported being employees and/or receiving grants or financial support from the company.

In an interview, Dr. Ali Hendi, assistant clinical professor of dermatology at Georgetown University Medical Center, Washington, said that he felt the investigators in the study were overly subjective in defining locally advanced tumors. "These are tumors that are aggressive, but that does not make them inoperable in the right hands," said Dr. Hendi, who is also a Mohs surgeon.

He also noted the slim complete response rate, which, when coupled with the toxicity and the high cost of the therapy – which might run as much as $70,000 per treatment course – make it a less desirable therapy for many patients.

"For locally advanced [disease] I think the utility is limited if there is good surgical care available," he said. Vismodegib may be more useful for BCC nevus syndrome and for metastatic disease, where it may be the only therapy available, he added.

Dr. Hendi reported no conflicts.

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.