Melanoma

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

ORLANDO – A novel hedgehog pathway inhibitor significantly and rapidly reduced the development of new basal cell carcinomas – as well as the size and severity of existing ones – in a randomized, controlled phase II study of 41 patients with basal cell nevus syndrome.

The number of new surgically eligible basal cell carcinomas (BCCs) that developed was 0.07/month in patients receiving active treatment with vismodegib (GDC-0449), compared with 1.74/month in those who received placebo (P less than .0001).

The change from baseline in the aggregate size of existing BCCs was –24 cm in the vismodegib group, compared with –3 cm in the placebo group (P = .006), Dr. Ervin H. Epstein Jr. reported at the annual meeting of the American Association for Cancer Research.

The investigator-initiated study was stopped at an interim analysis because of the highly statistically significant differences between the treatment and placebo groups.

"We have a drug, developed by Genentech, based on the fundamental knowledge that hedgehog signaling is pivotal to all BCCs – including in these patients who carry a defective copy of the gene that inhibits hedgehog signaling," said Dr. Epstein, senior scientist at Children’s Hospital of Oakland (Calif.) Research Institute.

"It is the first drug used in man that replaces the function of the missing gene ... and it actually works," added Dr. Epstein, who helped lay the foundation for the development of vismodegib in 1996 when, along with his colleagues, he identified the site of the mutation that causes basal cell nevus syndrome (the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway).

Patients from three clinical centers were enrolled from September 2009 to January 2011 in the current trial and were randomized 2:1 to receive 150 mg of vismodegib orally once daily, or placebo. Molecular analysis of samples from 23 subjects showed that anti-BCC efficacy was associated with on-target reduction of the hedgehog pathway; Gli1mRNA levels were decreased 200-fold after 1 month in BCCs of patients in the active treatment group, while levels remained unchanged in BCCs of patients in the placebo group.

Dr. Epstein showed several images demonstrating the dramatic improvement in patients with severe disease – sometimes as early as 1-2 months after treatment initiation, and noted that no resistance to treatment developed. Some patients achieved near remission. He cautioned, however, that the drug is associated with toxicity that makes it an unlikely treatment for "the usual patient with one BCC."

One fifth of participants discontinued the study because of toxicity. Common grade 1/2 adverse events were taste loss (in 83% of patients on treatment vs. 8% on placebo), muscle cramps (in 67% vs. 8%), and weight loss (in 50% vs. 8%). Hair loss also was common, which is not surprising, because the targeted pathway is important in hair follicle regeneration, Dr. Epstein explained.

Two grade 3/4 events occurred in patients in the study as well. These included muscle cramps, and a suicide attempt, he said.

While BCC is the most common type of cancer, affecting more than a million people in the United States each year – particularly those of European descent, most develop only one or a small number, and these can be managed with surgery, which currently can cure 98%-99% of cases, he said.

Only a very small number of patients – estimates range from 1/50,000 to 1/250,000 – have heritable conditions such as basal cell nevus syndrome (Gorlin's syndrome), which can be associated with the development of dozens, if not thousands, of lesions that require surgical management, and for these patients, the adverse events might be much more acceptable.

Indeed, for these patients this drug is "a breakthrough – with a capital B," said Dr. Daniel D. Von Hoff, physician-in-chief and distinguished professor at the Translational Genomics Research Institute (TGen) in Phoenix and moderator of an AACR press briefing during which Dr. Epstein discussed his findings.

Additional study is needed to assess long-term adverse events and to determine whether different dosing strategies would improve tolerance, Dr. Epstein said. Genentech has announced that is conducting an expanded patient access study while the company discusses its next steps with the U.S. Food and Drug Administration.

Dr. Epstein had no disclosures.

The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.

The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.

Ipilimumab is the first FDA-approved treatment "to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, noted in the announcement.

It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.

That the FDA did not specify a line of therapy "is extremely important and … will open the floodgates to this drug," Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.

"Most people with metastatic melanoma will see this drug," said Dr. Sosman, coauthor of the pivotal trial. The indication does not exclude untreated patients, he noted.

A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said "may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors." It is being studied in other cancers as well.

Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).

In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients.

On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO's annual meeting.

Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.

He described the durability of response with ipilimumab as "very good." Those with a true response (5%-10%) "do extremely well."

Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. "That's the group that actually gets the drug, their tumors seem to grow, but then they stabilize," so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes "a large group of patients who don't technically have a response, but have a durable stabilization of their disease," Dr. Sosman said.

The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)

"Physicians will have to be enlightened in how to manage these patients," Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy "can easily spiral out of control" and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.

Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. "It's a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for," he said.

Metastatic melanoma has been an "incredibly frustrating disease," with only one treatment – high dose interleukin-2 – approved since dacarbazine was approved in 1975, Dr. Sosman noted. The approval of interleukin-2 in 1998 was not based on overall survival benefit or high response rate, but the "incredible durability" among the subset of responders, about 5%-10% of those treated. "We used to consider melanoma the graveyard for phase III studies," with every study of regimens and drugs turning out negative, he said.

Dr. Sosman emphasized there is still a lot to learn, and that studies of treatment combinations are crucial, as these "may change the whole nature of the disease."He foresaw combining a drug that does not have a high response rate but has "incredible durability" with a drug such as a BRAF inhibitor, with "an extremely high response rate that causes a lot of tumor death rapidly and can even make a sick patient well."

He predicted that dacarbazine will fall by the wayside and will not be used in studies. It has a response rate of 5%-10% has never been shown to improve survival, and does not have a history of durability, he said.

Dr. Sosman disclosed that his institution received a grant from study sponsors BMS and Medarex for participating in the phase III trial.

* UPDATE: This article was updated on 3/28/2011.

The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.

The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.

Ipilimumab is the first FDA-approved treatment "to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, noted in the announcement.

It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.

That the FDA did not specify a line of therapy "is extremely important and … will open the floodgates to this drug," Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.

"Most people with metastatic melanoma will see this drug," said Dr. Sosman, coauthor of the pivotal trial. The indication does not exclude untreated patients, he noted.

A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said "may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors." It is being studied in other cancers as well.

Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).

In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients.

On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO's annual meeting.

Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.

He described the durability of response with ipilimumab as "very good." Those with a true response (5%-10%) "do extremely well."

Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. "That's the group that actually gets the drug, their tumors seem to grow, but then they stabilize," so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes "a large group of patients who don't technically have a response, but have a durable stabilization of their disease," Dr. Sosman said.

The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)

"Physicians will have to be enlightened in how to manage these patients," Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy "can easily spiral out of control" and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.

Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. "It's a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for," he said.

Metastatic melanoma has been an "incredibly frustrating disease," with only one treatment – high dose interleukin-2 – approved since dacarbazine was approved in 1975, Dr. Sosman noted. The approval of interleukin-2 in 1998 was not based on overall survival benefit or high response rate, but the "incredible durability" among the subset of responders, about 5%-10% of those treated. "We used to consider melanoma the graveyard for phase III studies," with every study of regimens and drugs turning out negative, he said.

Dr. Sosman emphasized there is still a lot to learn, and that studies of treatment combinations are crucial, as these "may change the whole nature of the disease."He foresaw combining a drug that does not have a high response rate but has "incredible durability" with a drug such as a BRAF inhibitor, with "an extremely high response rate that causes a lot of tumor death rapidly and can even make a sick patient well."

He predicted that dacarbazine will fall by the wayside and will not be used in studies. It has a response rate of 5%-10% has never been shown to improve survival, and does not have a history of durability, he said.

Dr. Sosman disclosed that his institution received a grant from study sponsors BMS and Medarex for participating in the phase III trial.

* UPDATE: This article was updated on 3/28/2011.

The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.

The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.

Ipilimumab is the first FDA-approved treatment "to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, noted in the announcement.

It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.

That the FDA did not specify a line of therapy "is extremely important and … will open the floodgates to this drug," Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.

"Most people with metastatic melanoma will see this drug," said Dr. Sosman, coauthor of the pivotal trial. The indication does not exclude untreated patients, he noted.

A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said "may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors." It is being studied in other cancers as well.

Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).

In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients.

On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO's annual meeting.

Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.

He described the durability of response with ipilimumab as "very good." Those with a true response (5%-10%) "do extremely well."

Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. "That's the group that actually gets the drug, their tumors seem to grow, but then they stabilize," so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes "a large group of patients who don't technically have a response, but have a durable stabilization of their disease," Dr. Sosman said.

The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)

"Physicians will have to be enlightened in how to manage these patients," Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy "can easily spiral out of control" and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.

Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. "It's a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for," he said.

Metastatic melanoma has been an "incredibly frustrating disease," with only one treatment – high dose interleukin-2 – approved since dacarbazine was approved in 1975, Dr. Sosman noted. The approval of interleukin-2 in 1998 was not based on overall survival benefit or high response rate, but the "incredible durability" among the subset of responders, about 5%-10% of those treated. "We used to consider melanoma the graveyard for phase III studies," with every study of regimens and drugs turning out negative, he said.

Dr. Sosman emphasized there is still a lot to learn, and that studies of treatment combinations are crucial, as these "may change the whole nature of the disease."He foresaw combining a drug that does not have a high response rate but has "incredible durability" with a drug such as a BRAF inhibitor, with "an extremely high response rate that causes a lot of tumor death rapidly and can even make a sick patient well."

He predicted that dacarbazine will fall by the wayside and will not be used in studies. It has a response rate of 5%-10% has never been shown to improve survival, and does not have a history of durability, he said.

Dr. Sosman disclosed that his institution received a grant from study sponsors BMS and Medarex for participating in the phase III trial.

* UPDATE: This article was updated on 3/28/2011.

The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.

The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.

Ipilimumab is the first FDA-approved treatment “to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment, Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, noted in the announcement.

It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.

That the FDA did not specify a line of therapy “is extremely important and … will open the floodgates to this drug,” Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.

“Most people with metastatic melanoma will see this drug,” said Dr. Sosman, coauthor of the pivotal trial and associate editor of The Oncology Report. The indication does not exclude untreated patients, he noted.

A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said “may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors.” It is being studied in other cancers as well.

Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).

In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients. On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO’s annual meeting.

Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.

He described the durability of response with ipilimumab as “very good.” Those with a true response (5%-10%) “do extremely well.”

Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. “That’s the group that actually gets the drug, their tumors seem to grow, but then they stabilize,” so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes “a large group of patients who don’t technically have a response, but have a durable stabilization of their disease,” Dr. Sosman said.

The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)

“Physicians will have to be enlightened in how to manage these patients,” Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy “can easily spiral out of control” and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.

Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. “It’s a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for,” he said.

Metastatic melanoma has been an “incredibly frustrating disease,” with only one treatment – high dose interleukin-2 – approved since dacarbazine was approved in 1975, Dr. Sosman noted. The approval of interleukin-2 in 1998 was not based on overall survival benefit or high response rate, but the “incredible durability” among the subset of responders, about 5%-10% of those treated. “We used to consider melanoma the graveyard for phase III studies,” with every study of regimens and drugs turning out negative, he said.

Dr. Sosman emphasized there is still a lot to learn, and that studies of treatment combinations are crucial, as these “may change the whole nature of the disease.” He foresaw combining a drug that does not have a high response rate but has “incredible durability” with a drug such as a BRAF inhibitor, with “an extremely high response rate that causes a lot of tumor death rapidly and can even make a sick patient well.”

He predicted that dacarbazine will fall by the wayside and will not be used in studies. It has a response rate of 5%-10% has never been shown to improve survival, and does not have a history of durability, he said.

Dr. Sosman disclosed that his institution received a grant from study sponsors BMS and Medarex for participating in the phase III trial.

* UPDATE: This article was updated on 3/28/2011.

The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.

The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.

Ipilimumab is the first FDA-approved treatment “to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment, Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, noted in the announcement.

It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.

That the FDA did not specify a line of therapy “is extremely important and … will open the floodgates to this drug,” Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.

“Most people with metastatic melanoma will see this drug,” said Dr. Sosman, coauthor of the pivotal trial and associate editor of The Oncology Report. The indication does not exclude untreated patients, he noted.

A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said “may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors.” It is being studied in other cancers as well.

Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).

In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients. On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO’s annual meeting.

Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.

He described the durability of response with ipilimumab as “very good.” Those with a true response (5%-10%) “do extremely well.”

Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. “That’s the group that actually gets the drug, their tumors seem to grow, but then they stabilize,” so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes “a large group of patients who don’t technically have a response, but have a durable stabilization of their disease,” Dr. Sosman said.

The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)

“Physicians will have to be enlightened in how to manage these patients,” Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy “can easily spiral out of control” and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.

Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. “It’s a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for,” he said.

Metastatic melanoma has been an “incredibly frustrating disease,” with only one treatment – high dose interleukin-2 – approved since dacarbazine was approved in 1975, Dr. Sosman noted. The approval of interleukin-2 in 1998 was not based on overall survival benefit or high response rate, but the “incredible durability” among the subset of responders, about 5%-10% of those treated. “We used to consider melanoma the graveyard for phase III studies,” with every study of regimens and drugs turning out negative, he said.

Dr. Sosman emphasized there is still a lot to learn, and that studies of treatment combinations are crucial, as these “may change the whole nature of the disease.” He foresaw combining a drug that does not have a high response rate but has “incredible durability” with a drug such as a BRAF inhibitor, with “an extremely high response rate that causes a lot of tumor death rapidly and can even make a sick patient well.”

He predicted that dacarbazine will fall by the wayside and will not be used in studies. It has a response rate of 5%-10% has never been shown to improve survival, and does not have a history of durability, he said.

Dr. Sosman disclosed that his institution received a grant from study sponsors BMS and Medarex for participating in the phase III trial.

* UPDATE: This article was updated on 3/28/2011.

The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.

The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.

Ipilimumab is the first FDA-approved treatment “to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment, Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, noted in the announcement.

It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.

That the FDA did not specify a line of therapy “is extremely important and … will open the floodgates to this drug,” Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.

“Most people with metastatic melanoma will see this drug,” said Dr. Sosman, coauthor of the pivotal trial and associate editor of The Oncology Report. The indication does not exclude untreated patients, he noted.

A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said “may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors.” It is being studied in other cancers as well.

Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).

In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients. On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO’s annual meeting.

Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.

He described the durability of response with ipilimumab as “very good.” Those with a true response (5%-10%) “do extremely well.”

Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. “That’s the group that actually gets the drug, their tumors seem to grow, but then they stabilize,” so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes “a large group of patients who don’t technically have a response, but have a durable stabilization of their disease,” Dr. Sosman said.

The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)

“Physicians will have to be enlightened in how to manage these patients,” Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy “can easily spiral out of control” and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.

Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. “It’s a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for,” he said.

Metastatic melanoma has been an “incredibly frustrating disease,” with only one treatment – high dose interleukin-2 – approved since dacarbazine was approved in 1975, Dr. Sosman noted. The approval of interleukin-2 in 1998 was not based on overall survival benefit or high response rate, but the “incredible durability” among the subset of responders, about 5%-10% of those treated. “We used to consider melanoma the graveyard for phase III studies,” with every study of regimens and drugs turning out negative, he said.

Dr. Sosman emphasized there is still a lot to learn, and that studies of treatment combinations are crucial, as these “may change the whole nature of the disease.” He foresaw combining a drug that does not have a high response rate but has “incredible durability” with a drug such as a BRAF inhibitor, with “an extremely high response rate that causes a lot of tumor death rapidly and can even make a sick patient well.”

He predicted that dacarbazine will fall by the wayside and will not be used in studies. It has a response rate of 5%-10% has never been shown to improve survival, and does not have a history of durability, he said.

Dr. Sosman disclosed that his institution received a grant from study sponsors BMS and Medarex for participating in the phase III trial.

* UPDATE: This article was updated on 3/28/2011.

The development of a serum glycoprotein microarray has led to the discovery of four proteins for which antibodies significantly predict nodal metastases in patients with melanoma, Dr. Michael Sabel explains. See the related story at http://tinyurl.com/5u3trew

The development of a serum glycoprotein microarray has led to the discovery of four proteins for which antibodies significantly predict nodal metastases in patients with melanoma, Dr. Michael Sabel explains. See the related story at http://tinyurl.com/5u3trew

The development of a serum glycoprotein microarray has led to the discovery of four proteins for which antibodies significantly predict nodal metastases in patients with melanoma, Dr. Michael Sabel explains. See the related story at http://tinyurl.com/5u3trew

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF). "Every melanoma patient is going to want it. But it's not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We've found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF). "Every melanoma patient is going to want it. But it's not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We've found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF). "Every melanoma patient is going to want it. But it's not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We've found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation. "Every melanoma patient is going to want it. But it’s not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We’ve found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation. "Every melanoma patient is going to want it. But it’s not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We’ve found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

WAILEA, HAWAII – Expect a flood of patient inquiries regarding ipilimumab beginning in late March, when it is widely expected to receive Food and Drug Administration marketing approval as the first new drug for melanoma in 13 years.

"This is the first drug ever shown to increase survival in patients with metastatic melanoma in a randomized study," Dr. Richard D. Carvajal said at the annual Hawaii Dermatology Seminar, sponsored by Skin Disease Education Foundation. "Every melanoma patient is going to want it. But it’s not for everybody."

For example, patients with rapidly progressive advanced disease may not be good candidates for ipilimumab, because the survival curves in the pivotal phase III clinical trial didn’t start to separate until about month 3. Ipilimumab affects the immune system, rather than directly targeting the tumor as do chemotherapy drugs. It takes some time for the ipilimumab-enhanced immune system to recognize the cancer and exert an antitumor effect, explained Dr. Carvajal, a medical oncologist in the melanoma and sarcoma service at Memorial Sloan-Kettering Cancer Center, New York.

Melanoma accounts for nearly 9,000 deaths annually in the United States. There is a dearth of treatment options for patients with advanced melanoma; indeed, the only FDA-approved treatments are dacarbazine (granted approval in 1975) and interleukin-2 (approved in 1998).

When chemotherapy works in advanced melanoma, it works quickly: A scan obtained after 6-8 weeks of therapy will show stability or shrinkage. That sort of response can also be seen with ipilimumab – but in addition, two novel patterns of response have been observed. One involves an initial increase in total tumor volume at the beginning of therapy, followed by delayed onset of stabilization or shrinkage.

Even more strikingly, some patients develop entirely new sites of metastatic disease when ipilimumab is started, with stabilization or shrinkage of both the new lesions and the baseline lesions coming several months later, according to Dr. Carvajal.

Ipilimumab is a fully human monoclonal antibody that binds to cytotoxic T lymphocyte–associated antigen 4 located on T cells. Inhibition of that antigen enhances the antitumor T-cell response. The administration schedule used in the clinical trials was one intravenous dose given every 3 weeks, for a total of four doses. Maintenance dosing at 12-week intervals has been employed in some studies.

The multicenter pivotal trial included 676 metastatic melanoma patients who were randomized to ipilimumab, a glycoprotein 100 peptide vaccine serving as placebo, or both. The 12-month survival rate was 46% with ipilimumab alone, compared with 25% with vaccine only; the 24-month survival rates were 23% and 14%. Median overall survival was 10.0 months with ipilimumab plus vaccine, 10.1 months with ipilimumab alone, and 6.4 months with vaccine only (N. Engl. J. Med. 2010;363:711-23).

Grade 3/4 immune-related toxicities associated with ipilimumab include diarrhea in about 4% of patients, rash or pruritus in 1%, and hepatitis, adrenal insufficiency, thyroiditis, or hypophysitis in fewer than 1% each.

"We’ve found that, if detected early, most of the toxicities are easily treated and reversible," Dr. Carvajal said. "The severity of toxicity is inversely related to the vigilance of surveillance, so we’re going to have to educate our medical oncology colleagues that they have to watch these patients quite closely. At any sign of bowel dysfunction – even increased gas – you have to initiate therapy to keep the diarrhea under control."

Caught early, the diarrhea is typically resolved or controlled within 2 weeks via high-dose oral corticosteroids, he added.

Vitiligo occurs in about 3% of treated patients. Depigmentation of hair and eyelashes has also been seen.

It appears that the patients who develop some type of immune side effect are more likely to have a beneficial response to treatment, according to Dr. Carvajal.

Efforts are ongoing to identify biomarkers that predict outcome so that ipilimumab can be employed selectively.

Bristol-Myers Squibb is developing ipilimumab. Dr. Carvajal has no financial relationship with the company, although he does serve as a consultant to Novartis regarding imatinib (Gleevec), another drug that is being developed as a novel therapy for melanoma. SDEF and this publication are owned by Elsevier.

SAN ANTONIO – Preoperative ultrasound assessment had an overall sensitivity of only 8% in the detection of positive sentinel lymph nodes among 2,481 patients with node-positive melanoma in the Multicenter Selective Lymphadenectomy Trial II.

"With a sensitivity of only 8% in this large, multicenter clinical trial, ultrasound is clearly not an effective substitute for sentinel node biopsy to detect metastatic disease and provide accurate staging," Dr. John F. Thompson said at a cancer symposium sponsored by the Society of Surgical Oncology.

As a result of the data, preoperative node field ultrasound has now been removed from the Multicenter Selective Lymphadenectomy Trial II (MSLT II) protocol.

The ongoing phase III MSLT II is designed to determine whether the melanoma-specific survival associated with sentinel lymphadenectomy and postoperative monitoring with serial nodal ultrasound is equivalent to that associated with sentinel lymphadenectomy plus complete lymph node dissection in stage IIa to IIIc melanoma patients with sentinel node (SN) metastases detected by histopathologic or molecular techniques.

Ultrasound has proven value in melanoma follow-up, leading some to suggest that preoperative ultrasound examination of regional nodes could provide accurate staging information and render sentinel node biopsy unnecessary.

To date the literature has been confusing. Some studies suggest high (65%) sensitivity (J. Clin. Oncol. 2009;27:4994-5000), while others suggest much lower (24%) sensitivity (J. Clin. Oncol. 2009;27:5614-9), Dr. Thompson said.

He presented data on 2,481 patients enrolled at 29 centers worldwide from December 2004 to March 2010 who underwent preoperative ultrasound assessment of their regional nodes, followed by sentinel node biopsy. Whether ultrasound was performed before or after the preoperative lymphoscintigraphy was at the discretion of the treating clinician. At 19 centers, excised sentinel nodes were examined pathologically with hematoxylin-eosin stain and immunohistochemistry and, if negative, by reverse transcriptase–polymerase chain reaction (RT-PCR) testing.

Sentinel nodes were removed from 2,788 lymph node fields in the 2,481 patients. Histopathology was positive in 578 fields in 554 patients. Among these, ultrasound was true positive in 46 and false negative in 532.

"Hardly an impressive result," said Dr. Thompson, professor of melanoma and surgical oncology at the University of Sydney and executive director of the Melanoma Institute Australia in North Sydney.

Among the 1,927 patients with 2,210 histologically negative lymph node fields, ultrasound was false positive in 52 and true negative in 1,771.

A total of 387 histologically negative, but RT-PCR-positive sentinel nodes were excluded from the ultrasound analysis because they would be expected to be picked up on ultrasound. However, seven of these cases were in fact reported positive on ultrasound, he said.

Of the remaining 2,401 lymph node fields, the overall sensitivity was 8%, specificity 97%, positive predictive value 47%, and negative predictive value 77%. Sensitivity was the highest at 55% in the axilla, and 0% in the popliteal and epitrochlear areas.

There was, of course, a learning curve with the ultrasound technology, Dr. Thompson noted. Sensitivity nearly doubled from 13% for the first 100 cases to 23% for the subsequent 100 cases. Specificity rose modestly from 93% to 95%.

As observed in other studies, the sensitivity of ultrasound increased with Breslow tumor thickness from just 2.6% for tumors 0-1 mm to 12% for those greater than 4 mm. "The positive predictive value at this stage is up around 81%, so you could perhaps make an argument for using ultrasound in thicker tumors," he said.

Finally, tumor burden data were available for 384 histologically positive sentinel nodes. As expected, the median cross-sectional area was larger at 4.80 mm² for sentinel nodes having ultrasound true-positive results vs. 0.12 mm² for those having ultrasound false-negative results. Significantly larger tumors were missed by ultrasound in the axilla when compared with the groin (P = .004).

"I think we can say that SN biopsy remains the most accurate method of regional node staging for patients with newly diagnosed melanoma," he concluded. "Sufficient accuracy cannot be achieved by assessing SNs using ultrasound alone."

MSLT II is sponsored by the John Wayne Cancer Institute. Dr. Thompson and his coauthors said they had no relevant financial disclosures.

SAN ANTONIO – Preoperative ultrasound assessment had an overall sensitivity of only 8% in the detection of positive sentinel lymph nodes among 2,481 patients with node-positive melanoma in the Multicenter Selective Lymphadenectomy Trial II.

"With a sensitivity of only 8% in this large, multicenter clinical trial, ultrasound is clearly not an effective substitute for sentinel node biopsy to detect metastatic disease and provide accurate staging," Dr. John F. Thompson said at a cancer symposium sponsored by the Society of Surgical Oncology.

As a result of the data, preoperative node field ultrasound has now been removed from the Multicenter Selective Lymphadenectomy Trial II (MSLT II) protocol.

The ongoing phase III MSLT II is designed to determine whether the melanoma-specific survival associated with sentinel lymphadenectomy and postoperative monitoring with serial nodal ultrasound is equivalent to that associated with sentinel lymphadenectomy plus complete lymph node dissection in stage IIa to IIIc melanoma patients with sentinel node (SN) metastases detected by histopathologic or molecular techniques.

Ultrasound has proven value in melanoma follow-up, leading some to suggest that preoperative ultrasound examination of regional nodes could provide accurate staging information and render sentinel node biopsy unnecessary.

To date the literature has been confusing. Some studies suggest high (65%) sensitivity (J. Clin. Oncol. 2009;27:4994-5000), while others suggest much lower (24%) sensitivity (J. Clin. Oncol. 2009;27:5614-9), Dr. Thompson said.

He presented data on 2,481 patients enrolled at 29 centers worldwide from December 2004 to March 2010 who underwent preoperative ultrasound assessment of their regional nodes, followed by sentinel node biopsy. Whether ultrasound was performed before or after the preoperative lymphoscintigraphy was at the discretion of the treating clinician. At 19 centers, excised sentinel nodes were examined pathologically with hematoxylin-eosin stain and immunohistochemistry and, if negative, by reverse transcriptase–polymerase chain reaction (RT-PCR) testing.

Sentinel nodes were removed from 2,788 lymph node fields in the 2,481 patients. Histopathology was positive in 578 fields in 554 patients. Among these, ultrasound was true positive in 46 and false negative in 532.

"Hardly an impressive result," said Dr. Thompson, professor of melanoma and surgical oncology at the University of Sydney and executive director of the Melanoma Institute Australia in North Sydney.

Among the 1,927 patients with 2,210 histologically negative lymph node fields, ultrasound was false positive in 52 and true negative in 1,771.

A total of 387 histologically negative, but RT-PCR-positive sentinel nodes were excluded from the ultrasound analysis because they would be expected to be picked up on ultrasound. However, seven of these cases were in fact reported positive on ultrasound, he said.

Of the remaining 2,401 lymph node fields, the overall sensitivity was 8%, specificity 97%, positive predictive value 47%, and negative predictive value 77%. Sensitivity was the highest at 55% in the axilla, and 0% in the popliteal and epitrochlear areas.

There was, of course, a learning curve with the ultrasound technology, Dr. Thompson noted. Sensitivity nearly doubled from 13% for the first 100 cases to 23% for the subsequent 100 cases. Specificity rose modestly from 93% to 95%.

As observed in other studies, the sensitivity of ultrasound increased with Breslow tumor thickness from just 2.6% for tumors 0-1 mm to 12% for those greater than 4 mm. "The positive predictive value at this stage is up around 81%, so you could perhaps make an argument for using ultrasound in thicker tumors," he said.

Finally, tumor burden data were available for 384 histologically positive sentinel nodes. As expected, the median cross-sectional area was larger at 4.80 mm² for sentinel nodes having ultrasound true-positive results vs. 0.12 mm² for those having ultrasound false-negative results. Significantly larger tumors were missed by ultrasound in the axilla when compared with the groin (P = .004).

"I think we can say that SN biopsy remains the most accurate method of regional node staging for patients with newly diagnosed melanoma," he concluded. "Sufficient accuracy cannot be achieved by assessing SNs using ultrasound alone."

MSLT II is sponsored by the John Wayne Cancer Institute. Dr. Thompson and his coauthors said they had no relevant financial disclosures.

SAN ANTONIO – Preoperative ultrasound assessment had an overall sensitivity of only 8% in the detection of positive sentinel lymph nodes among 2,481 patients with node-positive melanoma in the Multicenter Selective Lymphadenectomy Trial II.

"With a sensitivity of only 8% in this large, multicenter clinical trial, ultrasound is clearly not an effective substitute for sentinel node biopsy to detect metastatic disease and provide accurate staging," Dr. John F. Thompson said at a cancer symposium sponsored by the Society of Surgical Oncology.

As a result of the data, preoperative node field ultrasound has now been removed from the Multicenter Selective Lymphadenectomy Trial II (MSLT II) protocol.

The ongoing phase III MSLT II is designed to determine whether the melanoma-specific survival associated with sentinel lymphadenectomy and postoperative monitoring with serial nodal ultrasound is equivalent to that associated with sentinel lymphadenectomy plus complete lymph node dissection in stage IIa to IIIc melanoma patients with sentinel node (SN) metastases detected by histopathologic or molecular techniques.

Ultrasound has proven value in melanoma follow-up, leading some to suggest that preoperative ultrasound examination of regional nodes could provide accurate staging information and render sentinel node biopsy unnecessary.

To date the literature has been confusing. Some studies suggest high (65%) sensitivity (J. Clin. Oncol. 2009;27:4994-5000), while others suggest much lower (24%) sensitivity (J. Clin. Oncol. 2009;27:5614-9), Dr. Thompson said.

He presented data on 2,481 patients enrolled at 29 centers worldwide from December 2004 to March 2010 who underwent preoperative ultrasound assessment of their regional nodes, followed by sentinel node biopsy. Whether ultrasound was performed before or after the preoperative lymphoscintigraphy was at the discretion of the treating clinician. At 19 centers, excised sentinel nodes were examined pathologically with hematoxylin-eosin stain and immunohistochemistry and, if negative, by reverse transcriptase–polymerase chain reaction (RT-PCR) testing.

Sentinel nodes were removed from 2,788 lymph node fields in the 2,481 patients. Histopathology was positive in 578 fields in 554 patients. Among these, ultrasound was true positive in 46 and false negative in 532.

"Hardly an impressive result," said Dr. Thompson, professor of melanoma and surgical oncology at the University of Sydney and executive director of the Melanoma Institute Australia in North Sydney.

Among the 1,927 patients with 2,210 histologically negative lymph node fields, ultrasound was false positive in 52 and true negative in 1,771.

A total of 387 histologically negative, but RT-PCR-positive sentinel nodes were excluded from the ultrasound analysis because they would be expected to be picked up on ultrasound. However, seven of these cases were in fact reported positive on ultrasound, he said.

Of the remaining 2,401 lymph node fields, the overall sensitivity was 8%, specificity 97%, positive predictive value 47%, and negative predictive value 77%. Sensitivity was the highest at 55% in the axilla, and 0% in the popliteal and epitrochlear areas.

There was, of course, a learning curve with the ultrasound technology, Dr. Thompson noted. Sensitivity nearly doubled from 13% for the first 100 cases to 23% for the subsequent 100 cases. Specificity rose modestly from 93% to 95%.

As observed in other studies, the sensitivity of ultrasound increased with Breslow tumor thickness from just 2.6% for tumors 0-1 mm to 12% for those greater than 4 mm. "The positive predictive value at this stage is up around 81%, so you could perhaps make an argument for using ultrasound in thicker tumors," he said.

Finally, tumor burden data were available for 384 histologically positive sentinel nodes. As expected, the median cross-sectional area was larger at 4.80 mm² for sentinel nodes having ultrasound true-positive results vs. 0.12 mm² for those having ultrasound false-negative results. Significantly larger tumors were missed by ultrasound in the axilla when compared with the groin (P = .004).

"I think we can say that SN biopsy remains the most accurate method of regional node staging for patients with newly diagnosed melanoma," he concluded. "Sufficient accuracy cannot be achieved by assessing SNs using ultrasound alone."

MSLT II is sponsored by the John Wayne Cancer Institute. Dr. Thompson and his coauthors said they had no relevant financial disclosures.

SAN ANTONIO – Preoperative ultrasound assessment had an overall sensitivity of only 8% in the detection of positive sentinel lymph nodes among 2,481 patients with node-positive melanoma in the Multicenter Selective Lymphadenectomy Trial II.

"With a sensitivity of only 8% in this large, multicenter clinical trial, ultrasound is clearly not an effective substitute for sentinel node biopsy to detect metastatic disease and provide accurate staging," Dr. John F. Thompson said at a cancer symposium sponsored by the Society of Surgical Oncology.

As a result of the data, preoperative node field ultrasound has now been removed from the Multicenter Selective Lymphadenectomy Trial II (MSLT II) protocol.

The ongoing phase III MSLT II is designed to determine whether the melanoma-specific survival associated with sentinel lymphadenectomy and postoperative monitoring with serial nodal ultrasound is equivalent to that associated with sentinel lymphadenectomy plus complete lymph node dissection in stage IIa to IIIc melanoma patients with sentinel node (SN) metastases detected by histopathologic or molecular techniques.

Ultrasound has proven value in melanoma follow-up, leading some to suggest that preoperative ultrasound examination of regional nodes could provide accurate staging information and render sentinel node biopsy unnecessary.

To date the literature has been confusing. Some studies suggest high (65%) sensitivity (J. Clin. Oncol. 2009;27:4994-5000), while others suggest much lower (24%) sensitivity (J. Clin. Oncol. 2009;27:5614-9), Dr. Thompson said.

He presented data on 2,481 patients enrolled at 29 centers worldwide from December 2004 to March 2010 who underwent preoperative ultrasound assessment of their regional nodes, followed by sentinel node biopsy. Whether ultrasound was performed before or after the preoperative lymphoscintigraphy was at the discretion of the treating clinician. At 19 centers, excised sentinel nodes were examined pathologically with hematoxylin-eosin stain and immunohistochemistry and, if negative, by reverse transcriptase–polymerase chain reaction (RT-PCR) testing.

Sentinel nodes were removed from 2,788 lymph node fields in the 2,481 patients. Histopathology was positive in 578 fields in 554 patients. Among these, ultrasound was true positive in 46 and false negative in 532.

"Hardly an impressive result," said Dr. Thompson, professor of melanoma and surgical oncology at the University of Sydney and executive director of the Melanoma Institute Australia in North Sydney.

Among the 1,927 patients with 2,210 histologically negative lymph node fields, ultrasound was false positive in 52 and true negative in 1,771.

A total of 387 histologically negative, but RT-PCR–positive sentinel nodes were excluded from the ultrasound analysis because they would be expected to be picked up on ultrasound. However, seven of these cases were in fact reported positive on ultrasound, he said.

Of the remaining 2,401 lymph node fields, the overall sensitivity was 8%, specificity 97%, positive predictive value 47%, and negative predictive value 77%. Sensitivity was the highest at 55% in the axilla, and 0% in the popliteal and epitrochlear areas.

There was, of course, a learning curve with the ultrasound technology, Dr. Thompson noted. Sensitivity nearly doubled from 13% for the first 100 cases to 23% for the subsequent 100 cases. Specificity rose modestly from 93% to 95%.

As observed in other studies, the sensitivity of ultrasound increased with Breslow tumor thickness from just 2.6% for tumors 0-1 mm to 12% for those greater than 4 mm. "The positive predictive value at this stage is up around 81%, so you could perhaps make an argument for using ultrasound in thicker tumors," he said.

Finally, tumor burden data were available for 384 histologically positive sentinel nodes. As expected, the median cross-sectional area was larger at 4.80 mm² for sentinel nodes having ultrasound true-positive results vs. 0.12 mm² for those having ultrasound false-negative results. Significantly larger tumors were missed by ultrasound in the axilla when compared with the groin (P = .004).

"I think we can say that SN biopsy remains the most accurate method of regional node staging for patients with newly diagnosed melanoma," he concluded. "Sufficient accuracy cannot be achieved by assessing SNs using ultrasound alone."

MSLT II is sponsored by the John Wayne Cancer Institute. Dr. Thompson and his coauthors said they had no relevant financial disclosures.

SAN ANTONIO – Preoperative ultrasound assessment had an overall sensitivity of only 8% in the detection of positive sentinel lymph nodes among 2,481 patients with node-positive melanoma in the Multicenter Selective Lymphadenectomy Trial II.

"With a sensitivity of only 8% in this large, multicenter clinical trial, ultrasound is clearly not an effective substitute for sentinel node biopsy to detect metastatic disease and provide accurate staging," Dr. John F. Thompson said at a cancer symposium sponsored by the Society of Surgical Oncology.

As a result of the data, preoperative node field ultrasound has now been removed from the Multicenter Selective Lymphadenectomy Trial II (MSLT II) protocol.

The ongoing phase III MSLT II is designed to determine whether the melanoma-specific survival associated with sentinel lymphadenectomy and postoperative monitoring with serial nodal ultrasound is equivalent to that associated with sentinel lymphadenectomy plus complete lymph node dissection in stage IIa to IIIc melanoma patients with sentinel node (SN) metastases detected by histopathologic or molecular techniques.

Ultrasound has proven value in melanoma follow-up, leading some to suggest that preoperative ultrasound examination of regional nodes could provide accurate staging information and render sentinel node biopsy unnecessary.

To date the literature has been confusing. Some studies suggest high (65%) sensitivity (J. Clin. Oncol. 2009;27:4994-5000), while others suggest much lower (24%) sensitivity (J. Clin. Oncol. 2009;27:5614-9), Dr. Thompson said.

He presented data on 2,481 patients enrolled at 29 centers worldwide from December 2004 to March 2010 who underwent preoperative ultrasound assessment of their regional nodes, followed by sentinel node biopsy. Whether ultrasound was performed before or after the preoperative lymphoscintigraphy was at the discretion of the treating clinician. At 19 centers, excised sentinel nodes were examined pathologically with hematoxylin-eosin stain and immunohistochemistry and, if negative, by reverse transcriptase–polymerase chain reaction (RT-PCR) testing.

Sentinel nodes were removed from 2,788 lymph node fields in the 2,481 patients. Histopathology was positive in 578 fields in 554 patients. Among these, ultrasound was true positive in 46 and false negative in 532.

"Hardly an impressive result," said Dr. Thompson, professor of melanoma and surgical oncology at the University of Sydney and executive director of the Melanoma Institute Australia in North Sydney.

Among the 1,927 patients with 2,210 histologically negative lymph node fields, ultrasound was false positive in 52 and true negative in 1,771.

A total of 387 histologically negative, but RT-PCR–positive sentinel nodes were excluded from the ultrasound analysis because they would be expected to be picked up on ultrasound. However, seven of these cases were in fact reported positive on ultrasound, he said.

Of the remaining 2,401 lymph node fields, the overall sensitivity was 8%, specificity 97%, positive predictive value 47%, and negative predictive value 77%. Sensitivity was the highest at 55% in the axilla, and 0% in the popliteal and epitrochlear areas.

There was, of course, a learning curve with the ultrasound technology, Dr. Thompson noted. Sensitivity nearly doubled from 13% for the first 100 cases to 23% for the subsequent 100 cases. Specificity rose modestly from 93% to 95%.

As observed in other studies, the sensitivity of ultrasound increased with Breslow tumor thickness from just 2.6% for tumors 0-1 mm to 12% for those greater than 4 mm. "The positive predictive value at this stage is up around 81%, so you could perhaps make an argument for using ultrasound in thicker tumors," he said.

Finally, tumor burden data were available for 384 histologically positive sentinel nodes. As expected, the median cross-sectional area was larger at 4.80 mm² for sentinel nodes having ultrasound true-positive results vs. 0.12 mm² for those having ultrasound false-negative results. Significantly larger tumors were missed by ultrasound in the axilla when compared with the groin (P = .004).

"I think we can say that SN biopsy remains the most accurate method of regional node staging for patients with newly diagnosed melanoma," he concluded. "Sufficient accuracy cannot be achieved by assessing SNs using ultrasound alone."

MSLT II is sponsored by the John Wayne Cancer Institute. Dr. Thompson and his coauthors said they had no relevant financial disclosures.

SAN ANTONIO – Preoperative ultrasound assessment had an overall sensitivity of only 8% in the detection of positive sentinel lymph nodes among 2,481 patients with node-positive melanoma in the Multicenter Selective Lymphadenectomy Trial II.

"With a sensitivity of only 8% in this large, multicenter clinical trial, ultrasound is clearly not an effective substitute for sentinel node biopsy to detect metastatic disease and provide accurate staging," Dr. John F. Thompson said at a cancer symposium sponsored by the Society of Surgical Oncology.

As a result of the data, preoperative node field ultrasound has now been removed from the Multicenter Selective Lymphadenectomy Trial II (MSLT II) protocol.

The ongoing phase III MSLT II is designed to determine whether the melanoma-specific survival associated with sentinel lymphadenectomy and postoperative monitoring with serial nodal ultrasound is equivalent to that associated with sentinel lymphadenectomy plus complete lymph node dissection in stage IIa to IIIc melanoma patients with sentinel node (SN) metastases detected by histopathologic or molecular techniques.

Ultrasound has proven value in melanoma follow-up, leading some to suggest that preoperative ultrasound examination of regional nodes could provide accurate staging information and render sentinel node biopsy unnecessary.

To date the literature has been confusing. Some studies suggest high (65%) sensitivity (J. Clin. Oncol. 2009;27:4994-5000), while others suggest much lower (24%) sensitivity (J. Clin. Oncol. 2009;27:5614-9), Dr. Thompson said.

He presented data on 2,481 patients enrolled at 29 centers worldwide from December 2004 to March 2010 who underwent preoperative ultrasound assessment of their regional nodes, followed by sentinel node biopsy. Whether ultrasound was performed before or after the preoperative lymphoscintigraphy was at the discretion of the treating clinician. At 19 centers, excised sentinel nodes were examined pathologically with hematoxylin-eosin stain and immunohistochemistry and, if negative, by reverse transcriptase–polymerase chain reaction (RT-PCR) testing.

Sentinel nodes were removed from 2,788 lymph node fields in the 2,481 patients. Histopathology was positive in 578 fields in 554 patients. Among these, ultrasound was true positive in 46 and false negative in 532.

"Hardly an impressive result," said Dr. Thompson, professor of melanoma and surgical oncology at the University of Sydney and executive director of the Melanoma Institute Australia in North Sydney.

Among the 1,927 patients with 2,210 histologically negative lymph node fields, ultrasound was false positive in 52 and true negative in 1,771.

A total of 387 histologically negative, but RT-PCR–positive sentinel nodes were excluded from the ultrasound analysis because they would be expected to be picked up on ultrasound. However, seven of these cases were in fact reported positive on ultrasound, he said.

Of the remaining 2,401 lymph node fields, the overall sensitivity was 8%, specificity 97%, positive predictive value 47%, and negative predictive value 77%. Sensitivity was the highest at 55% in the axilla, and 0% in the popliteal and epitrochlear areas.

There was, of course, a learning curve with the ultrasound technology, Dr. Thompson noted. Sensitivity nearly doubled from 13% for the first 100 cases to 23% for the subsequent 100 cases. Specificity rose modestly from 93% to 95%.

As observed in other studies, the sensitivity of ultrasound increased with Breslow tumor thickness from just 2.6% for tumors 0-1 mm to 12% for those greater than 4 mm. "The positive predictive value at this stage is up around 81%, so you could perhaps make an argument for using ultrasound in thicker tumors," he said.

Finally, tumor burden data were available for 384 histologically positive sentinel nodes. As expected, the median cross-sectional area was larger at 4.80 mm² for sentinel nodes having ultrasound true-positive results vs. 0.12 mm² for those having ultrasound false-negative results. Significantly larger tumors were missed by ultrasound in the axilla when compared with the groin (P = .004).

"I think we can say that SN biopsy remains the most accurate method of regional node staging for patients with newly diagnosed melanoma," he concluded. "Sufficient accuracy cannot be achieved by assessing SNs using ultrasound alone."

MSLT II is sponsored by the John Wayne Cancer Institute. Dr. Thompson and his coauthors said they had no relevant financial disclosures.

Dr. Richard D. Carvajal discusses ipilimumab's outcomes, patterns of response, and potential side effects as a treatment for metastatic melanoma.

Dr. Richard D. Carvajal discusses ipilimumab's outcomes, patterns of response, and potential side effects as a treatment for metastatic melanoma.

Dr. Richard D. Carvajal discusses ipilimumab's outcomes, patterns of response, and potential side effects as a treatment for metastatic melanoma.