Melanoma

WHITE OAK, MD – The new sunscreen labeling regulations from the Food and Drug Administration should make it easier for dermatologists to spread the skin protection message and for consumers to select effective products, according to Dr. Ronald L. Moy.

"The FDA has now defined broad spectrum protection so consumers will better understand how to select a sunscreen that protects against skin cancer," said Dr. Moy, president of the American Academy of Dermatology. "We are encouraged that there are now simple, consistent labeling requirements."

He spoke at a press conference that was held to announce the new regulations and emphasized that skin cancer is a serious disease, and the number of cases in the United States are rising. "There are a few easy things you can do to protect your skin from ultraviolet radiation. And today the FDA’s new sunscreen labeling requirements make it even easier for us," he said. Current estimates are that one in five Americans will develop skin cancer in their lifetimes.

Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, presented the new labeling information at the press conference on June 14. After many years of deliberation and evaluation, the FDA defined the testing that a sunscreen product must undergo before it can make a claim of "broad-spectrum protection" on its label, meaning protection from both UVA and UVB radiation.

"These changes are part of an ongoing effort at the FDA to make sure that sunscreens meet standards for safety and efficacy," Dr. Woodcock said. "It wasn’t until recently that the FDA was able to establish an accurate and reliable broad-spectrum test," Dr. Woodcock said.

Based on the FDA test, the labels of broad-spectrum sunscreens with an SPF of at least 15 can state that, when used properly and with other protective measures, the products can help reduce the risk of skin cancer and the signs of premature aging.

"Only those products that pass the FDA test will be able to be labeled broad spectrum," Dr. Woodcock said. Some sunscreens with SPF in the 2 to 14 range that pass the FDA’s broad-spectrum test can be labeled as such, she said, but they will not be able to make claims related to skin cancer protection or anti-aging protection, according to the FDA rules.

As for concerns about nanoparticles in sunscreens, "the FDA does not currently have reason to warn consumers about their safety," Dr. Woodcock said. "We have performed testing and found that nanoparticles do not penetrate the skin. If we determine that any of the active ingredients do not meet the safety standards, the FDA will notify the public."

Dr. Woodcock and Dr. Moy had no financial conflicts to disclose.

WHITE OAK, MD – The new sunscreen labeling regulations from the Food and Drug Administration should make it easier for dermatologists to spread the skin protection message and for consumers to select effective products, according to Dr. Ronald L. Moy.

"The FDA has now defined broad spectrum protection so consumers will better understand how to select a sunscreen that protects against skin cancer," said Dr. Moy, president of the American Academy of Dermatology. "We are encouraged that there are now simple, consistent labeling requirements."

He spoke at a press conference that was held to announce the new regulations and emphasized that skin cancer is a serious disease, and the number of cases in the United States are rising. "There are a few easy things you can do to protect your skin from ultraviolet radiation. And today the FDA’s new sunscreen labeling requirements make it even easier for us," he said. Current estimates are that one in five Americans will develop skin cancer in their lifetimes.

Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, presented the new labeling information at the press conference on June 14. After many years of deliberation and evaluation, the FDA defined the testing that a sunscreen product must undergo before it can make a claim of "broad-spectrum protection" on its label, meaning protection from both UVA and UVB radiation.

"These changes are part of an ongoing effort at the FDA to make sure that sunscreens meet standards for safety and efficacy," Dr. Woodcock said. "It wasn’t until recently that the FDA was able to establish an accurate and reliable broad-spectrum test," Dr. Woodcock said.

Based on the FDA test, the labels of broad-spectrum sunscreens with an SPF of at least 15 can state that, when used properly and with other protective measures, the products can help reduce the risk of skin cancer and the signs of premature aging.

"Only those products that pass the FDA test will be able to be labeled broad spectrum," Dr. Woodcock said. Some sunscreens with SPF in the 2 to 14 range that pass the FDA’s broad-spectrum test can be labeled as such, she said, but they will not be able to make claims related to skin cancer protection or anti-aging protection, according to the FDA rules.

As for concerns about nanoparticles in sunscreens, "the FDA does not currently have reason to warn consumers about their safety," Dr. Woodcock said. "We have performed testing and found that nanoparticles do not penetrate the skin. If we determine that any of the active ingredients do not meet the safety standards, the FDA will notify the public."

Dr. Woodcock and Dr. Moy had no financial conflicts to disclose.

WHITE OAK, MD – The new sunscreen labeling regulations from the Food and Drug Administration should make it easier for dermatologists to spread the skin protection message and for consumers to select effective products, according to Dr. Ronald L. Moy.

"The FDA has now defined broad spectrum protection so consumers will better understand how to select a sunscreen that protects against skin cancer," said Dr. Moy, president of the American Academy of Dermatology. "We are encouraged that there are now simple, consistent labeling requirements."

He spoke at a press conference that was held to announce the new regulations and emphasized that skin cancer is a serious disease, and the number of cases in the United States are rising. "There are a few easy things you can do to protect your skin from ultraviolet radiation. And today the FDA’s new sunscreen labeling requirements make it even easier for us," he said. Current estimates are that one in five Americans will develop skin cancer in their lifetimes.

Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, presented the new labeling information at the press conference on June 14. After many years of deliberation and evaluation, the FDA defined the testing that a sunscreen product must undergo before it can make a claim of "broad-spectrum protection" on its label, meaning protection from both UVA and UVB radiation.

"These changes are part of an ongoing effort at the FDA to make sure that sunscreens meet standards for safety and efficacy," Dr. Woodcock said. "It wasn’t until recently that the FDA was able to establish an accurate and reliable broad-spectrum test," Dr. Woodcock said.

Based on the FDA test, the labels of broad-spectrum sunscreens with an SPF of at least 15 can state that, when used properly and with other protective measures, the products can help reduce the risk of skin cancer and the signs of premature aging.

"Only those products that pass the FDA test will be able to be labeled broad spectrum," Dr. Woodcock said. Some sunscreens with SPF in the 2 to 14 range that pass the FDA’s broad-spectrum test can be labeled as such, she said, but they will not be able to make claims related to skin cancer protection or anti-aging protection, according to the FDA rules.

As for concerns about nanoparticles in sunscreens, "the FDA does not currently have reason to warn consumers about their safety," Dr. Woodcock said. "We have performed testing and found that nanoparticles do not penetrate the skin. If we determine that any of the active ingredients do not meet the safety standards, the FDA will notify the public."

Dr. Woodcock and Dr. Moy had no financial conflicts to disclose.

WHITE OAK, MD – The new sunscreen labeling regulations from the Food and Drug Administration should make it easier for dermatologists to spread the skin protection message and for consumers to select effective products, according to Dr. Ronald L. Moy.

"The FDA has now defined broad spectrum protection so consumers will better understand how to select a sunscreen that protects against skin cancer," said Dr. Moy, president of the American Academy of Dermatology. "We are encouraged that there are now simple, consistent labeling requirements."

He spoke at a press conference that was held to announce the new regulations and emphasized that skin cancer is a serious disease, and the number of cases in the United States are rising. "There are a few easy things you can do to protect your skin from ultraviolet radiation. And today the FDA’s new sunscreen labeling requirements make it even easier for us," he said. Current estimates are that one in five Americans will develop skin cancer in their lifetimes.

Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, presented the new labeling information at the press conference on June 14. After many years of deliberation and evaluation, the FDA defined the testing that a sunscreen product must undergo before it can make a claim of "broad-spectrum protection" on its label, meaning protection from both UVA and UVB radiation.

"These changes are part of an ongoing effort at the FDA to make sure that sunscreens meet standards for safety and efficacy," Dr. Woodcock said. "It wasn't until recently that the FDA was able to establish an accurate and reliable broad-spectrum test," Dr. Woodcock said.

Based on the FDA test, the labels of broad-spectrum sunscreens with an SPF of at least 15 can state that, when used properly and with other protective measures, the products can help reduce the risk of skin cancer and the signs of premature aging.

"Only those products that pass the FDA test will be able to be labeled broad spectrum," Dr. Woodcock said. Some sunscreens with SPF in the 2 to 14 range that pass the FDA’s broad-spectrum test can be labeled as such, she said, but they will not be able to make claims related to skin cancer protection or anti-aging protection, according to the FDA rules.

As for concerns about nanoparticles in sunscreens, "the FDA does not currently have reason to warn consumers about their safety," Dr. Woodcock said. "We have performed testing and found that nanoparticles do not penetrate the skin. If we determine that any of the active ingredients do not meet the safety standards, the FDA will notify the public."

Dr. Woodcock and Dr. Moy had no financial conflicts to disclose.

WHITE OAK, MD – The new sunscreen labeling regulations from the Food and Drug Administration should make it easier for dermatologists to spread the skin protection message and for consumers to select effective products, according to Dr. Ronald L. Moy.

"The FDA has now defined broad spectrum protection so consumers will better understand how to select a sunscreen that protects against skin cancer," said Dr. Moy, president of the American Academy of Dermatology. "We are encouraged that there are now simple, consistent labeling requirements."

He spoke at a press conference that was held to announce the new regulations and emphasized that skin cancer is a serious disease, and the number of cases in the United States are rising. "There are a few easy things you can do to protect your skin from ultraviolet radiation. And today the FDA’s new sunscreen labeling requirements make it even easier for us," he said. Current estimates are that one in five Americans will develop skin cancer in their lifetimes.

Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, presented the new labeling information at the press conference on June 14. After many years of deliberation and evaluation, the FDA defined the testing that a sunscreen product must undergo before it can make a claim of "broad-spectrum protection" on its label, meaning protection from both UVA and UVB radiation.

"These changes are part of an ongoing effort at the FDA to make sure that sunscreens meet standards for safety and efficacy," Dr. Woodcock said. "It wasn't until recently that the FDA was able to establish an accurate and reliable broad-spectrum test," Dr. Woodcock said.

Based on the FDA test, the labels of broad-spectrum sunscreens with an SPF of at least 15 can state that, when used properly and with other protective measures, the products can help reduce the risk of skin cancer and the signs of premature aging.

"Only those products that pass the FDA test will be able to be labeled broad spectrum," Dr. Woodcock said. Some sunscreens with SPF in the 2 to 14 range that pass the FDA’s broad-spectrum test can be labeled as such, she said, but they will not be able to make claims related to skin cancer protection or anti-aging protection, according to the FDA rules.

As for concerns about nanoparticles in sunscreens, "the FDA does not currently have reason to warn consumers about their safety," Dr. Woodcock said. "We have performed testing and found that nanoparticles do not penetrate the skin. If we determine that any of the active ingredients do not meet the safety standards, the FDA will notify the public."

Dr. Woodcock and Dr. Moy had no financial conflicts to disclose.

WHITE OAK, MD – The new sunscreen labeling regulations from the Food and Drug Administration should make it easier for dermatologists to spread the skin protection message and for consumers to select effective products, according to Dr. Ronald L. Moy.

"The FDA has now defined broad spectrum protection so consumers will better understand how to select a sunscreen that protects against skin cancer," said Dr. Moy, president of the American Academy of Dermatology. "We are encouraged that there are now simple, consistent labeling requirements."

He spoke at a press conference that was held to announce the new regulations and emphasized that skin cancer is a serious disease, and the number of cases in the United States are rising. "There are a few easy things you can do to protect your skin from ultraviolet radiation. And today the FDA’s new sunscreen labeling requirements make it even easier for us," he said. Current estimates are that one in five Americans will develop skin cancer in their lifetimes.

Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, presented the new labeling information at the press conference on June 14. After many years of deliberation and evaluation, the FDA defined the testing that a sunscreen product must undergo before it can make a claim of "broad-spectrum protection" on its label, meaning protection from both UVA and UVB radiation.

"These changes are part of an ongoing effort at the FDA to make sure that sunscreens meet standards for safety and efficacy," Dr. Woodcock said. "It wasn't until recently that the FDA was able to establish an accurate and reliable broad-spectrum test," Dr. Woodcock said.

Based on the FDA test, the labels of broad-spectrum sunscreens with an SPF of at least 15 can state that, when used properly and with other protective measures, the products can help reduce the risk of skin cancer and the signs of premature aging.

"Only those products that pass the FDA test will be able to be labeled broad spectrum," Dr. Woodcock said. Some sunscreens with SPF in the 2 to 14 range that pass the FDA’s broad-spectrum test can be labeled as such, she said, but they will not be able to make claims related to skin cancer protection or anti-aging protection, according to the FDA rules.

As for concerns about nanoparticles in sunscreens, "the FDA does not currently have reason to warn consumers about their safety," Dr. Woodcock said. "We have performed testing and found that nanoparticles do not penetrate the skin. If we determine that any of the active ingredients do not meet the safety standards, the FDA will notify the public."

Dr. Woodcock and Dr. Moy had no financial conflicts to disclose.

The Food and Drug Administration has issued new rules on sunscreen labeling to help consumers select products that prevent sunburn and reduce the risk of skin cancer and early skin aging.

The new labeling will differentiate sunscreen products according to their protective properties. Those products that meet FDA requirements of protection from ultraviolet A (UVA) and ultraviolet B (UVB) will be labeled "Broad Spectrum."

Photo courtesy FDA

UVA and UVB radiation are known to contribute to sunburn, skin cancer, and premature skin aging. Under the new rules, only products that qualify as broad spectrum and have SPF values of 15 (or higher) can include labeling that the product helps prevent skin cancer and reduces the risk of early skin aging. Other products with SPF values between 2 and 14 may be labeled broad spectrum if they meet FDA tests for UVA and UVB protection, but will be required to have a warning stating that the product has not been shown to prevent skin cancer or early skin aging.

"FDA has evaluated the data and developed testing and labeling requirements for sunscreen products, so that manufacturers can modernize their product information and consumers can be well-informed on which products offer the greatest benefit," said Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research. "These changes to sunscreen labels are an important part of helping consumers have the information they need so they can choose the right sun protection for themselves and their families."

The new regulations will go into effective in 1 year for most manufacturers. Other sunscreen makers with annual sales of less than $25,000 will have 2 years to comply with the new rules.

The Food and Drug Administration has issued new rules on sunscreen labeling to help consumers select products that prevent sunburn and reduce the risk of skin cancer and early skin aging.

The new labeling will differentiate sunscreen products according to their protective properties. Those products that meet FDA requirements of protection from ultraviolet A (UVA) and ultraviolet B (UVB) will be labeled "Broad Spectrum."

Photo courtesy FDA

UVA and UVB radiation are known to contribute to sunburn, skin cancer, and premature skin aging. Under the new rules, only products that qualify as broad spectrum and have SPF values of 15 (or higher) can include labeling that the product helps prevent skin cancer and reduces the risk of early skin aging. Other products with SPF values between 2 and 14 may be labeled broad spectrum if they meet FDA tests for UVA and UVB protection, but will be required to have a warning stating that the product has not been shown to prevent skin cancer or early skin aging.

"FDA has evaluated the data and developed testing and labeling requirements for sunscreen products, so that manufacturers can modernize their product information and consumers can be well-informed on which products offer the greatest benefit," said Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research. "These changes to sunscreen labels are an important part of helping consumers have the information they need so they can choose the right sun protection for themselves and their families."

The new regulations will go into effective in 1 year for most manufacturers. Other sunscreen makers with annual sales of less than $25,000 will have 2 years to comply with the new rules.

The Food and Drug Administration has issued new rules on sunscreen labeling to help consumers select products that prevent sunburn and reduce the risk of skin cancer and early skin aging.

The new labeling will differentiate sunscreen products according to their protective properties. Those products that meet FDA requirements of protection from ultraviolet A (UVA) and ultraviolet B (UVB) will be labeled "Broad Spectrum."

Photo courtesy FDA

UVA and UVB radiation are known to contribute to sunburn, skin cancer, and premature skin aging. Under the new rules, only products that qualify as broad spectrum and have SPF values of 15 (or higher) can include labeling that the product helps prevent skin cancer and reduces the risk of early skin aging. Other products with SPF values between 2 and 14 may be labeled broad spectrum if they meet FDA tests for UVA and UVB protection, but will be required to have a warning stating that the product has not been shown to prevent skin cancer or early skin aging.

"FDA has evaluated the data and developed testing and labeling requirements for sunscreen products, so that manufacturers can modernize their product information and consumers can be well-informed on which products offer the greatest benefit," said Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research. "These changes to sunscreen labels are an important part of helping consumers have the information they need so they can choose the right sun protection for themselves and their families."

The new regulations will go into effective in 1 year for most manufacturers. Other sunscreen makers with annual sales of less than $25,000 will have 2 years to comply with the new rules.

LAS VEGAS – A perioperative hemorrhage in a patient undergoing Mohs surgery is a bloody mess, but a thrombosis causing a stroke is a catastrophe.

"Bleeding is overemphasized in our specialty, because it's dramatic. But it is very inconsequential in contrast to thrombosis, which is probably underappreciated," Dr. Clark C. Otley said at the annual meeting of the American College of Mohs Surgery.

Photo credit: Courtesy Dr. Clark C. Otley 

He reviewed the literature on the risks for hemorrhage in patients on anticoagulant therapy who undergo Mohs surgery and the risks for thrombosis in patients who stop their anticoagulant therapy before Mohs.

"The bottom line is that bleeding happens, but nobody dies. That's in contrast to the thrombotic data, where people do die," said Dr. Otley, professor of dermatology at the Mayo Clinic, Rochester, Minn.

The consequences of a thrombotic episode are so much greater than the impact of a hemorrhagic complication that he recommended continuing medically necessary anticoagulants in most cases. "Take extra care with clopidogrel plus aspirin and with warfarin. Taking patients off these, especially if they have a fresh stent, is not the right thing to do," he said.

A survey of 168 American College of Mohs Surgery members in 2003 gathered reports of thrombotic complications within 3 days of Mohs surgery in 46 patients who had stopped anticoagulant therapy, Dr. Otley noted. These included stroke in 24 patients, transient ischemic attack in 8, MI in 5, cerebral emboli or death in 3 patients each, pulmonary embolus in 2, and blindness in 1 patient (J. Am. Acad. Dermatol 2003;48:233-7).

A separate survey of more than 270 dermasurgeons in 2005 found thrombotic complications in 126 patients who stopped anticoagulants for Mohs surgery, including stroke in 39 patients, transient ischemic attack in 25, MI in 19, unstable angina in 17, death in 15, deep venous thrombosis in 7, and pulmonary embolus in 4 patients (Dermatol. Surg. 2007;33:1189-97).

Case reports are emerging of thrombotic episodes in patients on newer anticoagulants who stop therapy for cutaneous surgery. For instance, he noted, a patient who stopped ticlopidine and aspirin developed a deep venous thrombosis. A patient who stopped clopidogrel and ardeparin thrombosed a prosthetic valve. A patient who stopped clopidogrel and aspirin had an MI.

These problems typically present as emergencies, which the Mohs surgeon may not see, Dr. Otley noted. "You may have had more patients experience this than you know about," he said.

Most of the data on the risk of hemorrhagic complications in patients undergoing superficial cutaneous surgery while on anticoagulants focus on traditional agents such as warfarin, aspirin, and NSAIDs, with some data on heparin. Little or no data exist on the risks with newer, more potent anticoagulants.

A total of 10 of 11 studies of patients on warfarin, aspirin, or NSAIDs found no increased risk of perioperative severe hemorrhagic complications, Dr. Otley said. One study of 21 patients on warfarin found an increased risk of complications including persistent bleeding, hematoma, infection, or graft loss. The most severe complication observed in any of the 11 studies was hematoma.

A meta-analysis of the data found a significantly increased risk if moderate and severe hemorrhagic complications were combined as an outcome, but not for severe complications alone, he noted (Dermatol. Surg. 2008;34:160-5).

Clopidogrel (Plavix) is new enough that there is little consensus on how to manage patients on this potent anticoagulant during cutaneous surgery. "This is the one that we’re seeing a ton of patients on," Dr. Otley said. "If your patient has a fresh stent, you would be insane to take that patient off this medication."

Patients on clopidogrel usually are on other anticoagulants, too. Data suggest there is a significant 28-fold higher risk of severe hemorrhagic complications in patients on any clopidogrel-containing regimen, compared with patients not taking anticoagulants, and a significant eightfold higher risk in patients on clopidogrel plus aspirin, compared with patients on aspirin alone. If you compare patients on clopidogrel with patients not on anticoagulant therapy, the difference in risk for severe hemorrhagic complications is not significant, probably due to the small number of patients on clopidogrel alone, he said.

"Nobody has died of hemorrhagic complications, to my knowledge," while having cutaneous surgery on clopidogrel. However, stopping the drug increases the risk of death from thrombotic complications, Dr. Otley said.

There are no data yet on cutaneous surgery complications in patients on dabigatran, "the new kid on the block," and a drug that "you're going to be hearing a lot about," he said. Dabigatran is as effective as warfarin for preventing stroke in high-risk patients.

If patients scheduled for Mohs surgery are on dabigatran, "I'd probably have them continue it unless your hematologist says otherwise," Dr. Otley said. He urged Mohs surgeons to start collecting data on any complications in patients on dabigatran.

To prevent bleeding complications from Mohs surgery, pay attention to hematologic parameters and monitor blood pressure. Hypertension is the leading cause of excessive intraoperative bleeding, he said. Administer sedatives for anxiolysis, use epinephrine as needed, apply pressure dressings, and put in a drain if you think a patient is going to bleed. Use blood products if needed.

In the OR, dislodge temporary clots, eliminate dead space, apply pressure dressings, and use other techniques for secondary prevention of bleeding complications, he advised. "There's no better time to have someone bleed than while you have them open, so rub all those clots off and recoagulate," he said.

Patients with hemorrhagic complications often apologize to Dr. Otley, thinking they did something that caused the bleeding. "I can guarantee you thrombotic patients will not be apologizing to you," he said.

Dr. Otley said he has no relevant conflicts of interest.

LAS VEGAS – A perioperative hemorrhage in a patient undergoing Mohs surgery is a bloody mess, but a thrombosis causing a stroke is a catastrophe.

"Bleeding is overemphasized in our specialty, because it's dramatic. But it is very inconsequential in contrast to thrombosis, which is probably underappreciated," Dr. Clark C. Otley said at the annual meeting of the American College of Mohs Surgery.

Photo credit: Courtesy Dr. Clark C. Otley 

He reviewed the literature on the risks for hemorrhage in patients on anticoagulant therapy who undergo Mohs surgery and the risks for thrombosis in patients who stop their anticoagulant therapy before Mohs.

"The bottom line is that bleeding happens, but nobody dies. That's in contrast to the thrombotic data, where people do die," said Dr. Otley, professor of dermatology at the Mayo Clinic, Rochester, Minn.

The consequences of a thrombotic episode are so much greater than the impact of a hemorrhagic complication that he recommended continuing medically necessary anticoagulants in most cases. "Take extra care with clopidogrel plus aspirin and with warfarin. Taking patients off these, especially if they have a fresh stent, is not the right thing to do," he said.

A survey of 168 American College of Mohs Surgery members in 2003 gathered reports of thrombotic complications within 3 days of Mohs surgery in 46 patients who had stopped anticoagulant therapy, Dr. Otley noted. These included stroke in 24 patients, transient ischemic attack in 8, MI in 5, cerebral emboli or death in 3 patients each, pulmonary embolus in 2, and blindness in 1 patient (J. Am. Acad. Dermatol 2003;48:233-7).

A separate survey of more than 270 dermasurgeons in 2005 found thrombotic complications in 126 patients who stopped anticoagulants for Mohs surgery, including stroke in 39 patients, transient ischemic attack in 25, MI in 19, unstable angina in 17, death in 15, deep venous thrombosis in 7, and pulmonary embolus in 4 patients (Dermatol. Surg. 2007;33:1189-97).

Case reports are emerging of thrombotic episodes in patients on newer anticoagulants who stop therapy for cutaneous surgery. For instance, he noted, a patient who stopped ticlopidine and aspirin developed a deep venous thrombosis. A patient who stopped clopidogrel and ardeparin thrombosed a prosthetic valve. A patient who stopped clopidogrel and aspirin had an MI.

These problems typically present as emergencies, which the Mohs surgeon may not see, Dr. Otley noted. "You may have had more patients experience this than you know about," he said.

Most of the data on the risk of hemorrhagic complications in patients undergoing superficial cutaneous surgery while on anticoagulants focus on traditional agents such as warfarin, aspirin, and NSAIDs, with some data on heparin. Little or no data exist on the risks with newer, more potent anticoagulants.

A total of 10 of 11 studies of patients on warfarin, aspirin, or NSAIDs found no increased risk of perioperative severe hemorrhagic complications, Dr. Otley said. One study of 21 patients on warfarin found an increased risk of complications including persistent bleeding, hematoma, infection, or graft loss. The most severe complication observed in any of the 11 studies was hematoma.

A meta-analysis of the data found a significantly increased risk if moderate and severe hemorrhagic complications were combined as an outcome, but not for severe complications alone, he noted (Dermatol. Surg. 2008;34:160-5).

Clopidogrel (Plavix) is new enough that there is little consensus on how to manage patients on this potent anticoagulant during cutaneous surgery. "This is the one that we’re seeing a ton of patients on," Dr. Otley said. "If your patient has a fresh stent, you would be insane to take that patient off this medication."

Patients on clopidogrel usually are on other anticoagulants, too. Data suggest there is a significant 28-fold higher risk of severe hemorrhagic complications in patients on any clopidogrel-containing regimen, compared with patients not taking anticoagulants, and a significant eightfold higher risk in patients on clopidogrel plus aspirin, compared with patients on aspirin alone. If you compare patients on clopidogrel with patients not on anticoagulant therapy, the difference in risk for severe hemorrhagic complications is not significant, probably due to the small number of patients on clopidogrel alone, he said.

"Nobody has died of hemorrhagic complications, to my knowledge," while having cutaneous surgery on clopidogrel. However, stopping the drug increases the risk of death from thrombotic complications, Dr. Otley said.

There are no data yet on cutaneous surgery complications in patients on dabigatran, "the new kid on the block," and a drug that "you're going to be hearing a lot about," he said. Dabigatran is as effective as warfarin for preventing stroke in high-risk patients.

If patients scheduled for Mohs surgery are on dabigatran, "I'd probably have them continue it unless your hematologist says otherwise," Dr. Otley said. He urged Mohs surgeons to start collecting data on any complications in patients on dabigatran.

To prevent bleeding complications from Mohs surgery, pay attention to hematologic parameters and monitor blood pressure. Hypertension is the leading cause of excessive intraoperative bleeding, he said. Administer sedatives for anxiolysis, use epinephrine as needed, apply pressure dressings, and put in a drain if you think a patient is going to bleed. Use blood products if needed.

In the OR, dislodge temporary clots, eliminate dead space, apply pressure dressings, and use other techniques for secondary prevention of bleeding complications, he advised. "There's no better time to have someone bleed than while you have them open, so rub all those clots off and recoagulate," he said.

Patients with hemorrhagic complications often apologize to Dr. Otley, thinking they did something that caused the bleeding. "I can guarantee you thrombotic patients will not be apologizing to you," he said.

Dr. Otley said he has no relevant conflicts of interest.

LAS VEGAS – A perioperative hemorrhage in a patient undergoing Mohs surgery is a bloody mess, but a thrombosis causing a stroke is a catastrophe.

"Bleeding is overemphasized in our specialty, because it's dramatic. But it is very inconsequential in contrast to thrombosis, which is probably underappreciated," Dr. Clark C. Otley said at the annual meeting of the American College of Mohs Surgery.

Photo credit: Courtesy Dr. Clark C. Otley 

He reviewed the literature on the risks for hemorrhage in patients on anticoagulant therapy who undergo Mohs surgery and the risks for thrombosis in patients who stop their anticoagulant therapy before Mohs.

"The bottom line is that bleeding happens, but nobody dies. That's in contrast to the thrombotic data, where people do die," said Dr. Otley, professor of dermatology at the Mayo Clinic, Rochester, Minn.

The consequences of a thrombotic episode are so much greater than the impact of a hemorrhagic complication that he recommended continuing medically necessary anticoagulants in most cases. "Take extra care with clopidogrel plus aspirin and with warfarin. Taking patients off these, especially if they have a fresh stent, is not the right thing to do," he said.

A survey of 168 American College of Mohs Surgery members in 2003 gathered reports of thrombotic complications within 3 days of Mohs surgery in 46 patients who had stopped anticoagulant therapy, Dr. Otley noted. These included stroke in 24 patients, transient ischemic attack in 8, MI in 5, cerebral emboli or death in 3 patients each, pulmonary embolus in 2, and blindness in 1 patient (J. Am. Acad. Dermatol 2003;48:233-7).

A separate survey of more than 270 dermasurgeons in 2005 found thrombotic complications in 126 patients who stopped anticoagulants for Mohs surgery, including stroke in 39 patients, transient ischemic attack in 25, MI in 19, unstable angina in 17, death in 15, deep venous thrombosis in 7, and pulmonary embolus in 4 patients (Dermatol. Surg. 2007;33:1189-97).

Case reports are emerging of thrombotic episodes in patients on newer anticoagulants who stop therapy for cutaneous surgery. For instance, he noted, a patient who stopped ticlopidine and aspirin developed a deep venous thrombosis. A patient who stopped clopidogrel and ardeparin thrombosed a prosthetic valve. A patient who stopped clopidogrel and aspirin had an MI.

These problems typically present as emergencies, which the Mohs surgeon may not see, Dr. Otley noted. "You may have had more patients experience this than you know about," he said.

Most of the data on the risk of hemorrhagic complications in patients undergoing superficial cutaneous surgery while on anticoagulants focus on traditional agents such as warfarin, aspirin, and NSAIDs, with some data on heparin. Little or no data exist on the risks with newer, more potent anticoagulants.

A total of 10 of 11 studies of patients on warfarin, aspirin, or NSAIDs found no increased risk of perioperative severe hemorrhagic complications, Dr. Otley said. One study of 21 patients on warfarin found an increased risk of complications including persistent bleeding, hematoma, infection, or graft loss. The most severe complication observed in any of the 11 studies was hematoma.

A meta-analysis of the data found a significantly increased risk if moderate and severe hemorrhagic complications were combined as an outcome, but not for severe complications alone, he noted (Dermatol. Surg. 2008;34:160-5).

Clopidogrel (Plavix) is new enough that there is little consensus on how to manage patients on this potent anticoagulant during cutaneous surgery. "This is the one that we’re seeing a ton of patients on," Dr. Otley said. "If your patient has a fresh stent, you would be insane to take that patient off this medication."

Patients on clopidogrel usually are on other anticoagulants, too. Data suggest there is a significant 28-fold higher risk of severe hemorrhagic complications in patients on any clopidogrel-containing regimen, compared with patients not taking anticoagulants, and a significant eightfold higher risk in patients on clopidogrel plus aspirin, compared with patients on aspirin alone. If you compare patients on clopidogrel with patients not on anticoagulant therapy, the difference in risk for severe hemorrhagic complications is not significant, probably due to the small number of patients on clopidogrel alone, he said.

"Nobody has died of hemorrhagic complications, to my knowledge," while having cutaneous surgery on clopidogrel. However, stopping the drug increases the risk of death from thrombotic complications, Dr. Otley said.

There are no data yet on cutaneous surgery complications in patients on dabigatran, "the new kid on the block," and a drug that "you're going to be hearing a lot about," he said. Dabigatran is as effective as warfarin for preventing stroke in high-risk patients.

If patients scheduled for Mohs surgery are on dabigatran, "I'd probably have them continue it unless your hematologist says otherwise," Dr. Otley said. He urged Mohs surgeons to start collecting data on any complications in patients on dabigatran.

To prevent bleeding complications from Mohs surgery, pay attention to hematologic parameters and monitor blood pressure. Hypertension is the leading cause of excessive intraoperative bleeding, he said. Administer sedatives for anxiolysis, use epinephrine as needed, apply pressure dressings, and put in a drain if you think a patient is going to bleed. Use blood products if needed.

In the OR, dislodge temporary clots, eliminate dead space, apply pressure dressings, and use other techniques for secondary prevention of bleeding complications, he advised. "There's no better time to have someone bleed than while you have them open, so rub all those clots off and recoagulate," he said.

Patients with hemorrhagic complications often apologize to Dr. Otley, thinking they did something that caused the bleeding. "I can guarantee you thrombotic patients will not be apologizing to you," he said.

Dr. Otley said he has no relevant conflicts of interest.

BOSTON – Healthy individuals do not need to be screened for vitamin D deficiency, according to guidelines released today by the Endocrine Society.

"We do not recommend screening for vitamin D deficiency in individuals not at risk. That's an important message. So we're recommending screening for those at risk for vitamin D deficiency – those who are obese, African Americans, pregnant and lactating women, patients with malabsorption syndromes, and a whole list that we have provided in the guidelines," lead author Dr. Michael F. Holick said at the annual meeting of the Endocrine Society.

Photo Credit: © Kaspri/Fotolia.com

Dr. Holick headed a task force appointed by the clinical guidelines subcommittee of the Endocrine Society to formulate evidence-based recommendations on vitamin D deficiency. The subcommittee deemed vitamin D deficiency a priority area in need of practice guidelines.

The task force noted that most individuals do not get adequate vitamin D for a number of reasons. In particular, "there needs to be an appreciation that unprotected sun exposure is the major source of vitamin D for both children and adults and that in the absence of sun exposure it is difficult, if not impossible, to obtain an adequate amount of vitamin D from dietary sources without supplementation to satisfy the body’s requirement. Concerns about melanoma and other types of skin cancer necessitate avoidance of excessive exposure to midday sun," they wrote.

The task force recommended that those at risk for vitamin D deficiency be screened by measuring serum 25-hydroxyvitamin D levels using a reliable assay. Causes of vitamin D deficiency include obesity, fat malabsorption syndromes, bariatric surgery, nephrotic syndrome, a wide range of medications (anticonvulsants and anti–HIV/AIDS drugs), chronic granuloma-forming disorders, some lymphomas, and primary hyperthyroidism.

The guidelines were released at the meeting and will be published in the July issue of the Journal of Clinical Endocrinology & Metabolism (doi: 10.1210/jc.2011-0385).

The guidelines provide long-awaited recommendations on vitamin D intake and the diagnosis and treatment of vitamin D deficiency. Physicians have struggled for years to delineate how much vitamin D is necessary for different clinical groups, how to measure it, and how best to supplement deficiencies.

The task force commissioned the conduct of two systematic reviews of the literature to inform its key recommendations and followed the approach recommended by GRADE, an international group with expertise in development and implementation of evidence-based guidelines.

"All available evidence suggests that children and adults should maintain a blood level of 25(OH)D above 20 ng/mL to prevent rickets and osteomalacia, respectively. However, to maximize vitamin D's effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/mL," the group wrote.

In the new guidelines, vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L). The task force suggests:

– Infants and children aged 0-1 year require at least 400 IU/day (IU = 25 ng) of vitamin D to maximize bone health.

– Children 1 year and older require at least 600 IU/day.

– Adults aged 19-50 years require at least 600 IU/day.

– Adults aged 50-70 years require at least 600 IU/day.

– Adults 70 years and older require 800 IU/day.

– Pregnant and lactating women require at least 600 IU/day.

The task force also recommends that obese children and adults and children and adults on certain medications (anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS) be given at least 2-3 times more vitamin D for their age group to satisfy their bodies' vitamin D requirements.

Either vitamin D₂ or vitamin D₃ can be used for the treatment and prevention of vitamin D deficiency. The group recommends that adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for eight weeks or its equivalent of 6,000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D greater than 30 ng/mL. This should be followed by maintenance therapy of 1,500-2,000 IU/day.

The task force also recommends vitamin D supplementation for fall prevention. "We know that there is sufficient evidence to give vitamin D for fall prevention. It's well documented that vitamin D is very important for muscle strength," said Dr. Holick, professor of medicine, physiology and biophysics at Boston University.

However, the group does not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life, because there is insufficient evidence.

The guidelines are cosponsored by the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation.

All but one of the authors reported having significant financial relationships with pharmaceutical companies, medical organizations, and/or food industry groups.

BOSTON – Healthy individuals do not need to be screened for vitamin D deficiency, according to guidelines released today by the Endocrine Society.

"We do not recommend screening for vitamin D deficiency in individuals not at risk. That's an important message. So we're recommending screening for those at risk for vitamin D deficiency – those who are obese, African Americans, pregnant and lactating women, patients with malabsorption syndromes, and a whole list that we have provided in the guidelines," lead author Dr. Michael F. Holick said at the annual meeting of the Endocrine Society.

Photo Credit: © Kaspri/Fotolia.com

Dr. Holick headed a task force appointed by the clinical guidelines subcommittee of the Endocrine Society to formulate evidence-based recommendations on vitamin D deficiency. The subcommittee deemed vitamin D deficiency a priority area in need of practice guidelines.

The task force noted that most individuals do not get adequate vitamin D for a number of reasons. In particular, "there needs to be an appreciation that unprotected sun exposure is the major source of vitamin D for both children and adults and that in the absence of sun exposure it is difficult, if not impossible, to obtain an adequate amount of vitamin D from dietary sources without supplementation to satisfy the body’s requirement. Concerns about melanoma and other types of skin cancer necessitate avoidance of excessive exposure to midday sun," they wrote.

The task force recommended that those at risk for vitamin D deficiency be screened by measuring serum 25-hydroxyvitamin D levels using a reliable assay. Causes of vitamin D deficiency include obesity, fat malabsorption syndromes, bariatric surgery, nephrotic syndrome, a wide range of medications (anticonvulsants and anti–HIV/AIDS drugs), chronic granuloma-forming disorders, some lymphomas, and primary hyperthyroidism.

The guidelines were released at the meeting and will be published in the July issue of the Journal of Clinical Endocrinology & Metabolism (doi: 10.1210/jc.2011-0385).

The guidelines provide long-awaited recommendations on vitamin D intake and the diagnosis and treatment of vitamin D deficiency. Physicians have struggled for years to delineate how much vitamin D is necessary for different clinical groups, how to measure it, and how best to supplement deficiencies.

The task force commissioned the conduct of two systematic reviews of the literature to inform its key recommendations and followed the approach recommended by GRADE, an international group with expertise in development and implementation of evidence-based guidelines.

"All available evidence suggests that children and adults should maintain a blood level of 25(OH)D above 20 ng/mL to prevent rickets and osteomalacia, respectively. However, to maximize vitamin D's effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/mL," the group wrote.

In the new guidelines, vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L). The task force suggests:

– Infants and children aged 0-1 year require at least 400 IU/day (IU = 25 ng) of vitamin D to maximize bone health.

– Children 1 year and older require at least 600 IU/day.

– Adults aged 19-50 years require at least 600 IU/day.

– Adults aged 50-70 years require at least 600 IU/day.

– Adults 70 years and older require 800 IU/day.

– Pregnant and lactating women require at least 600 IU/day.

The task force also recommends that obese children and adults and children and adults on certain medications (anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS) be given at least 2-3 times more vitamin D for their age group to satisfy their bodies' vitamin D requirements.

Either vitamin D₂ or vitamin D₃ can be used for the treatment and prevention of vitamin D deficiency. The group recommends that adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for eight weeks or its equivalent of 6,000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D greater than 30 ng/mL. This should be followed by maintenance therapy of 1,500-2,000 IU/day.

The task force also recommends vitamin D supplementation for fall prevention. "We know that there is sufficient evidence to give vitamin D for fall prevention. It's well documented that vitamin D is very important for muscle strength," said Dr. Holick, professor of medicine, physiology and biophysics at Boston University.

However, the group does not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life, because there is insufficient evidence.

The guidelines are cosponsored by the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation.

All but one of the authors reported having significant financial relationships with pharmaceutical companies, medical organizations, and/or food industry groups.

BOSTON – Healthy individuals do not need to be screened for vitamin D deficiency, according to guidelines released today by the Endocrine Society.

"We do not recommend screening for vitamin D deficiency in individuals not at risk. That's an important message. So we're recommending screening for those at risk for vitamin D deficiency – those who are obese, African Americans, pregnant and lactating women, patients with malabsorption syndromes, and a whole list that we have provided in the guidelines," lead author Dr. Michael F. Holick said at the annual meeting of the Endocrine Society.

Photo Credit: © Kaspri/Fotolia.com

Dr. Holick headed a task force appointed by the clinical guidelines subcommittee of the Endocrine Society to formulate evidence-based recommendations on vitamin D deficiency. The subcommittee deemed vitamin D deficiency a priority area in need of practice guidelines.

The task force noted that most individuals do not get adequate vitamin D for a number of reasons. In particular, "there needs to be an appreciation that unprotected sun exposure is the major source of vitamin D for both children and adults and that in the absence of sun exposure it is difficult, if not impossible, to obtain an adequate amount of vitamin D from dietary sources without supplementation to satisfy the body’s requirement. Concerns about melanoma and other types of skin cancer necessitate avoidance of excessive exposure to midday sun," they wrote.

The task force recommended that those at risk for vitamin D deficiency be screened by measuring serum 25-hydroxyvitamin D levels using a reliable assay. Causes of vitamin D deficiency include obesity, fat malabsorption syndromes, bariatric surgery, nephrotic syndrome, a wide range of medications (anticonvulsants and anti–HIV/AIDS drugs), chronic granuloma-forming disorders, some lymphomas, and primary hyperthyroidism.

The guidelines were released at the meeting and will be published in the July issue of the Journal of Clinical Endocrinology & Metabolism (doi: 10.1210/jc.2011-0385).

The guidelines provide long-awaited recommendations on vitamin D intake and the diagnosis and treatment of vitamin D deficiency. Physicians have struggled for years to delineate how much vitamin D is necessary for different clinical groups, how to measure it, and how best to supplement deficiencies.

The task force commissioned the conduct of two systematic reviews of the literature to inform its key recommendations and followed the approach recommended by GRADE, an international group with expertise in development and implementation of evidence-based guidelines.

"All available evidence suggests that children and adults should maintain a blood level of 25(OH)D above 20 ng/mL to prevent rickets and osteomalacia, respectively. However, to maximize vitamin D's effect on calcium, bone, and muscle metabolism, the 25(OH)D blood level should be above 30 ng/mL," the group wrote.

In the new guidelines, vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L). The task force suggests:

– Infants and children aged 0-1 year require at least 400 IU/day (IU = 25 ng) of vitamin D to maximize bone health.

– Children 1 year and older require at least 600 IU/day.

– Adults aged 19-50 years require at least 600 IU/day.

– Adults aged 50-70 years require at least 600 IU/day.

– Adults 70 years and older require 800 IU/day.

– Pregnant and lactating women require at least 600 IU/day.

The task force also recommends that obese children and adults and children and adults on certain medications (anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS) be given at least 2-3 times more vitamin D for their age group to satisfy their bodies' vitamin D requirements.

Either vitamin D₂ or vitamin D₃ can be used for the treatment and prevention of vitamin D deficiency. The group recommends that adults who are vitamin D deficient be treated with 50,000 IU of vitamin D₂ or vitamin D₃ once a week for eight weeks or its equivalent of 6,000 IU of vitamin D₂ or vitamin D₃ daily to achieve a blood level of 25(OH)D greater than 30 ng/mL. This should be followed by maintenance therapy of 1,500-2,000 IU/day.

The task force also recommends vitamin D supplementation for fall prevention. "We know that there is sufficient evidence to give vitamin D for fall prevention. It's well documented that vitamin D is very important for muscle strength," said Dr. Holick, professor of medicine, physiology and biophysics at Boston University.

However, the group does not recommend prescribing vitamin D supplementation beyond recommended daily needs for the purpose of preventing cardiovascular disease or death or improving quality of life, because there is insufficient evidence.

The guidelines are cosponsored by the Canadian Society of Endocrinology and Metabolism and the National Osteoporosis Foundation.

All but one of the authors reported having significant financial relationships with pharmaceutical companies, medical organizations, and/or food industry groups.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m², three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

CHICAGO — A closely watched experimental drug has come through with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients.

Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.

The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial.

The prospect of two new drugs for advanced melanoma is "really unprecedented," said Dr. Lynn Schuchter, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where BRIM-3 results were presented in a plenary session. They were published simultaneously in the New England Journal of Medicine (2011 June 5;10.1956NEJMOa1103782).

The BRIM-3 study and ipilimumab data also presented at the meeting will provide the foundation for further research into how to optimize therapy for the disease, said Dr. Schuchter, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Pittsburgh.

Indeed, just how to incorporate both drugs into clinical practice was a hot topic at the meeting, as up to now oncologists have had few therapeutic options to offer patients with advanced melanoma.

"It’s wonderful to have this problem. The melanoma community is still trying to sort this out," said Dr. Paul Chapman, lead author of the BRIM-3 study and an attending-physician at Memorial Sloan-Kettering Cancer Center in New York. The drug companies developing both drugs– Bristol-Myers Squibb behind ipilimumab and Genentech behind vemurafenib – are already planning a study of them in combination, he added.

Among the dramatic early results from BRIM-3, Dr. Chapman reported estimates that 84% of patients treated with oral vemurafenib but only 64% of those given dacarbazine (DTIC) would be alive at 6 months. The hazard ratio for death was 0.37 (P less than .0001), and an analysis of progression-free survival showed a 74% reduction in the risk of progression (HR 0.26, P less than .0001). Median time to progression was 5.3 months with vemurafenib vs. 1.6 months with dacarbazine, he said.

Dacarbazine, a standard therapy since 1975 for melanoma, produced a response in only 5.5% of patients in the control group. In contrast, 48.4% responded to the new agent. These benefits were seen in all subgroups, including those with M1c disease and high lactate dehydrogenase levels.

The trial screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47%, and accrued 675 patients from January 2010 though December 2010. The median age was in the mid-50s, and more than half of patients were men.

Participants were randomized to 960 mg of vemurafenib orally twice a day or 1,000 mg/m² of dacarbazine by intravenous infusion every 3 weeks. A double-blind study would have been difficult but doable, Dr. Chapman said; the Food and Drug Administration made the decision to do BRIM-3 as an open label trial.

A larger study was planned, but a data safety monitoring board halted the trial in December after an interim analysis. Although the original protocol did not call for crossover of patients from the control group to active therapy, Dr. Chapman said crossover was allowed because of the striking advantage demonstrated by vemurafenib.

Following the extraordinarily early closing of the trial, median follow-up was only 3 months in the data reported as of the end of 2010. Median survival has not been reached in the patients treated with vemurafenib, Dr. Chapman said, but is typically less than 8 months with dacarbazine.

He expressed optimism that the advantage would hold up over time. The Kaplan Meier survival curve "tracks almost perfectly" with that presented at the same meeting by Dr. Antoni Ribas of the phase II BRIM-2 study, which had a median follow-up of 7 months and an overall response rate of 53%. In that study, Dr. Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported, median overall survival had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months.

Some patients in BRIM-3 had not been enrolled long enough to be assessed, Dr. Chapman said, adding that 7 of 32 patients in the initial phase I trial were still being treated.

Despite periods of remission that are long for metastatic melanoma, most patients eventually experience disease recurrence on vemurafenib. Despite the experience so far, the investigators are hoping that some patients will survive long-term, Dr. Chapman said.

The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.

The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.

As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.

In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.

In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.

As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.

Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures.

CHICAGO — A closely watched experimental drug has come through with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients.

Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.

The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial.

The prospect of two new drugs for advanced melanoma is "really unprecedented," said Dr. Lynn Schuchter, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where BRIM-3 results were presented in a plenary session. They were published simultaneously in the New England Journal of Medicine (2011 June 5;10.1956NEJMOa1103782).

The BRIM-3 study and ipilimumab data also presented at the meeting will provide the foundation for further research into how to optimize therapy for the disease, said Dr. Schuchter, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Pittsburgh.

Indeed, just how to incorporate both drugs into clinical practice was a hot topic at the meeting, as up to now oncologists have had few therapeutic options to offer patients with advanced melanoma.

"It’s wonderful to have this problem. The melanoma community is still trying to sort this out," said Dr. Paul Chapman, lead author of the BRIM-3 study and an attending-physician at Memorial Sloan-Kettering Cancer Center in New York. The drug companies developing both drugs– Bristol-Myers Squibb behind ipilimumab and Genentech behind vemurafenib – are already planning a study of them in combination, he added.

Among the dramatic early results from BRIM-3, Dr. Chapman reported estimates that 84% of patients treated with oral vemurafenib but only 64% of those given dacarbazine (DTIC) would be alive at 6 months. The hazard ratio for death was 0.37 (P less than .0001), and an analysis of progression-free survival showed a 74% reduction in the risk of progression (HR 0.26, P less than .0001). Median time to progression was 5.3 months with vemurafenib vs. 1.6 months with dacarbazine, he said.

Dacarbazine, a standard therapy since 1975 for melanoma, produced a response in only 5.5% of patients in the control group. In contrast, 48.4% responded to the new agent. These benefits were seen in all subgroups, including those with M1c disease and high lactate dehydrogenase levels.

The trial screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47%, and accrued 675 patients from January 2010 though December 2010. The median age was in the mid-50s, and more than half of patients were men.

Participants were randomized to 960 mg of vemurafenib orally twice a day or 1,000 mg/m² of dacarbazine by intravenous infusion every 3 weeks. A double-blind study would have been difficult but doable, Dr. Chapman said; the Food and Drug Administration made the decision to do BRIM-3 as an open label trial.

A larger study was planned, but a data safety monitoring board halted the trial in December after an interim analysis. Although the original protocol did not call for crossover of patients from the control group to active therapy, Dr. Chapman said crossover was allowed because of the striking advantage demonstrated by vemurafenib.

Following the extraordinarily early closing of the trial, median follow-up was only 3 months in the data reported as of the end of 2010. Median survival has not been reached in the patients treated with vemurafenib, Dr. Chapman said, but is typically less than 8 months with dacarbazine.

He expressed optimism that the advantage would hold up over time. The Kaplan Meier survival curve "tracks almost perfectly" with that presented at the same meeting by Dr. Antoni Ribas of the phase II BRIM-2 study, which had a median follow-up of 7 months and an overall response rate of 53%. In that study, Dr. Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported, median overall survival had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months.

Some patients in BRIM-3 had not been enrolled long enough to be assessed, Dr. Chapman said, adding that 7 of 32 patients in the initial phase I trial were still being treated.

Despite periods of remission that are long for metastatic melanoma, most patients eventually experience disease recurrence on vemurafenib. Despite the experience so far, the investigators are hoping that some patients will survive long-term, Dr. Chapman said.

The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.

The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.

As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.

In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.

In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.

As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.

Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures.

CHICAGO — A closely watched experimental drug has come through with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients.

Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.

The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial.

The prospect of two new drugs for advanced melanoma is "really unprecedented," said Dr. Lynn Schuchter, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where BRIM-3 results were presented in a plenary session. They were published simultaneously in the New England Journal of Medicine (2011 June 5;10.1956NEJMOa1103782).

The BRIM-3 study and ipilimumab data also presented at the meeting will provide the foundation for further research into how to optimize therapy for the disease, said Dr. Schuchter, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Pittsburgh.

Indeed, just how to incorporate both drugs into clinical practice was a hot topic at the meeting, as up to now oncologists have had few therapeutic options to offer patients with advanced melanoma.

"It’s wonderful to have this problem. The melanoma community is still trying to sort this out," said Dr. Paul Chapman, lead author of the BRIM-3 study and an attending-physician at Memorial Sloan-Kettering Cancer Center in New York. The drug companies developing both drugs– Bristol-Myers Squibb behind ipilimumab and Genentech behind vemurafenib – are already planning a study of them in combination, he added.

Among the dramatic early results from BRIM-3, Dr. Chapman reported estimates that 84% of patients treated with oral vemurafenib but only 64% of those given dacarbazine (DTIC) would be alive at 6 months. The hazard ratio for death was 0.37 (P less than .0001), and an analysis of progression-free survival showed a 74% reduction in the risk of progression (HR 0.26, P less than .0001). Median time to progression was 5.3 months with vemurafenib vs. 1.6 months with dacarbazine, he said.

Dacarbazine, a standard therapy since 1975 for melanoma, produced a response in only 5.5% of patients in the control group. In contrast, 48.4% responded to the new agent. These benefits were seen in all subgroups, including those with M1c disease and high lactate dehydrogenase levels.

The trial screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47%, and accrued 675 patients from January 2010 though December 2010. The median age was in the mid-50s, and more than half of patients were men.

Participants were randomized to 960 mg of vemurafenib orally twice a day or 1,000 mg/m² of dacarbazine by intravenous infusion every 3 weeks. A double-blind study would have been difficult but doable, Dr. Chapman said; the Food and Drug Administration made the decision to do BRIM-3 as an open label trial.

A larger study was planned, but a data safety monitoring board halted the trial in December after an interim analysis. Although the original protocol did not call for crossover of patients from the control group to active therapy, Dr. Chapman said crossover was allowed because of the striking advantage demonstrated by vemurafenib.

Following the extraordinarily early closing of the trial, median follow-up was only 3 months in the data reported as of the end of 2010. Median survival has not been reached in the patients treated with vemurafenib, Dr. Chapman said, but is typically less than 8 months with dacarbazine.

He expressed optimism that the advantage would hold up over time. The Kaplan Meier survival curve "tracks almost perfectly" with that presented at the same meeting by Dr. Antoni Ribas of the phase II BRIM-2 study, which had a median follow-up of 7 months and an overall response rate of 53%. In that study, Dr. Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported, median overall survival had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months.

Some patients in BRIM-3 had not been enrolled long enough to be assessed, Dr. Chapman said, adding that 7 of 32 patients in the initial phase I trial were still being treated.

Despite periods of remission that are long for metastatic melanoma, most patients eventually experience disease recurrence on vemurafenib. Despite the experience so far, the investigators are hoping that some patients will survive long-term, Dr. Chapman said.

The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.

The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.

As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.

In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.

In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.

As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.

Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures.

CHICAGO — A closely watched experimental drug has come through with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients.

Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.

The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial.

The prospect of two new drugs for advanced melanoma is "really unprecedented," said Dr. Lynn Schuchter, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where BRIM-3 results were presented in a plenary session. They were published simultaneously in the New England Journal of Medicine (10.1956NEJMOa1103782).

The BRIM-3 study and ipilimumab data also presented at the meeting will provide the foundation for further research into how to optimize therapy for the disease, said Dr. Schuchter, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Pittsburgh.

Indeed, just how to incorporate both drugs into clinical practice was a hot topic at the meeting, as up to now oncologists have had few therapeutic options to offer patients with advanced melanoma.

"It’s wonderful to have this problem. The melanoma community is still trying to sort this out," said Dr. Paul Chapman, lead author of the BRIM-3 study and an attending-physician at Memorial Sloan-Kettering Cancer Center in New York. The drug companies developing both drugs– Bristol-Myers Squibb behind ipilimumab and Genentech behind vemurafenib – are already planning a study of them in combination, he added.

Among the dramatic early results from BRIM-3, Dr. Chapman reported estimates that 84% of patients treated with oral vemurafenib but only 64% of those given dacarbazine (DTIC) would be alive at 6 months. The hazard ratio for death was 0.37 (P less than .0001), and an analysis of progression-free survival showed a 74% reduction in the risk of progression (HR 0.26, P less than .0001). Median time to progression was 5.3 months with vemurafenib vs. 1.6 months with dacarbazine, he said.

Dacarbazine, a standard therapy since 1975 for melanoma, produced a response in only 5.5% of patients in the control group. In contrast, 48.4% responded to the new agent. These benefits were seen in all subgroups, including those with M1c disease and high lactate dehydrogenase levels.

The trial screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47%, and accrued 675 patients from January 2010 though December 2010. The median age was in the mid-50s, and more than half of patients were men.

Participants were randomized to 960 mg of vemurafenib orally twice a day or 1,000 mg/m² of dacarbazine by intravenous infusion every 3 weeks. A double-blind study would have been difficult but doable, Dr. Chapman said; the Food and Drug Administration made the decision to do BRIM-3 as an open label trial.

A larger study was planned, but a data safety monitoring board halted the trial in December after an interim analysis. Although the original protocol did not call for crossover of patients from the control group to active therapy, Dr. Chapman said crossover was allowed because of the striking advantage demonstrated by vemurafenib.

Following the extraordinarily early closing of the trial, median follow-up was only 3 months in the data reported as of the end of 2010. Median survival has not been reached in the patients treated with vemurafenib, Dr. Chapman said, but is typically less than 8 months with dacarbazine.

He expressed optimism that the advantage would hold up over time. The Kaplan Meier survival curve "tracks almost perfectly" with that presented at the same meeting by Dr. Antoni Ribas of the phase II BRIM-2 study, which had a median follow-up of 7 months and an overall response rate of 53%. In that study, Dr. Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported, median overall survival had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months.

Some patients in BRIM-3 had not been enrolled long enough to be assessed, Dr. Chapman said, adding that 7 of 32 patients in the initial phase I trial were still being treated.

Despite periods of remission that are long for metastatic melanoma, most patients eventually experience disease recurrence on vemurafenib. Despite the experience so far, the investigators are hoping that some patients will survive long-term, Dr. Chapman said.

The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.

The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.

As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.

In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.

In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.

As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.

Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures. Dr. Ernstoff made no relevant financial conflicts of interest.

CHICAGO — A closely watched experimental drug has come through with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients.

Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.

The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial.

The prospect of two new drugs for advanced melanoma is "really unprecedented," said Dr. Lynn Schuchter, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where BRIM-3 results were presented in a plenary session. They were published simultaneously in the New England Journal of Medicine (10.1956NEJMOa1103782).

The BRIM-3 study and ipilimumab data also presented at the meeting will provide the foundation for further research into how to optimize therapy for the disease, said Dr. Schuchter, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Pittsburgh.

Indeed, just how to incorporate both drugs into clinical practice was a hot topic at the meeting, as up to now oncologists have had few therapeutic options to offer patients with advanced melanoma.

"It’s wonderful to have this problem. The melanoma community is still trying to sort this out," said Dr. Paul Chapman, lead author of the BRIM-3 study and an attending-physician at Memorial Sloan-Kettering Cancer Center in New York. The drug companies developing both drugs– Bristol-Myers Squibb behind ipilimumab and Genentech behind vemurafenib – are already planning a study of them in combination, he added.

Among the dramatic early results from BRIM-3, Dr. Chapman reported estimates that 84% of patients treated with oral vemurafenib but only 64% of those given dacarbazine (DTIC) would be alive at 6 months. The hazard ratio for death was 0.37 (P less than .0001), and an analysis of progression-free survival showed a 74% reduction in the risk of progression (HR 0.26, P less than .0001). Median time to progression was 5.3 months with vemurafenib vs. 1.6 months with dacarbazine, he said.

Dacarbazine, a standard therapy since 1975 for melanoma, produced a response in only 5.5% of patients in the control group. In contrast, 48.4% responded to the new agent. These benefits were seen in all subgroups, including those with M1c disease and high lactate dehydrogenase levels.

The trial screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47%, and accrued 675 patients from January 2010 though December 2010. The median age was in the mid-50s, and more than half of patients were men.

Participants were randomized to 960 mg of vemurafenib orally twice a day or 1,000 mg/m² of dacarbazine by intravenous infusion every 3 weeks. A double-blind study would have been difficult but doable, Dr. Chapman said; the Food and Drug Administration made the decision to do BRIM-3 as an open label trial.

A larger study was planned, but a data safety monitoring board halted the trial in December after an interim analysis. Although the original protocol did not call for crossover of patients from the control group to active therapy, Dr. Chapman said crossover was allowed because of the striking advantage demonstrated by vemurafenib.

Following the extraordinarily early closing of the trial, median follow-up was only 3 months in the data reported as of the end of 2010. Median survival has not been reached in the patients treated with vemurafenib, Dr. Chapman said, but is typically less than 8 months with dacarbazine.

He expressed optimism that the advantage would hold up over time. The Kaplan Meier survival curve "tracks almost perfectly" with that presented at the same meeting by Dr. Antoni Ribas of the phase II BRIM-2 study, which had a median follow-up of 7 months and an overall response rate of 53%. In that study, Dr. Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported, median overall survival had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months.

Some patients in BRIM-3 had not been enrolled long enough to be assessed, Dr. Chapman said, adding that 7 of 32 patients in the initial phase I trial were still being treated.

Despite periods of remission that are long for metastatic melanoma, most patients eventually experience disease recurrence on vemurafenib. Despite the experience so far, the investigators are hoping that some patients will survive long-term, Dr. Chapman said.

The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.

The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.

As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.

In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.

In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.

As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.

Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures. Dr. Ernstoff made no relevant financial conflicts of interest.

CHICAGO — A closely watched experimental drug has come through with a 63% reduction in the relative risk of death from metastatic melanoma when compared with standard therapy in a phase III trial that had enrolled 675 newly diagnosed patients.

Vemurafenib (better known as PLX4032) targets the BRAF V600E mutation found in 40%-60% of melanoma patients. It is only the second melanoma drug to extend the lives of melanoma patients in a randomized clinical study.

The first such agent, ipilimumab (Yervoy), was approved earlier this year, and the melanoma community expects the Food and Drug Administration will award an indication to vemurafenib based on the new data from the BRIM-3 trial.

The prospect of two new drugs for advanced melanoma is "really unprecedented," said Dr. Lynn Schuchter, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where BRIM-3 results were presented in a plenary session. They were published simultaneously in the New England Journal of Medicine (10.1956NEJMOa1103782).

The BRIM-3 study and ipilimumab data also presented at the meeting will provide the foundation for further research into how to optimize therapy for the disease, said Dr. Schuchter, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Pittsburgh.

Indeed, just how to incorporate both drugs into clinical practice was a hot topic at the meeting, as up to now oncologists have had few therapeutic options to offer patients with advanced melanoma.

"It’s wonderful to have this problem. The melanoma community is still trying to sort this out," said Dr. Paul Chapman, lead author of the BRIM-3 study and an attending-physician at Memorial Sloan-Kettering Cancer Center in New York. The drug companies developing both drugs– Bristol-Myers Squibb behind ipilimumab and Genentech behind vemurafenib – are already planning a study of them in combination, he added.

Among the dramatic early results from BRIM-3, Dr. Chapman reported estimates that 84% of patients treated with oral vemurafenib but only 64% of those given dacarbazine (DTIC) would be alive at 6 months. The hazard ratio for death was 0.37 (P less than .0001), and an analysis of progression-free survival showed a 74% reduction in the risk of progression (HR 0.26, P less than .0001). Median time to progression was 5.3 months with vemurafenib vs. 1.6 months with dacarbazine, he said.

Dacarbazine, a standard therapy since 1975 for melanoma, produced a response in only 5.5% of patients in the control group. In contrast, 48.4% responded to the new agent. These benefits were seen in all subgroups, including those with M1c disease and high lactate dehydrogenase levels.

The trial screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47%, and accrued 675 patients from January 2010 though December 2010. The median age was in the mid-50s, and more than half of patients were men.

Participants were randomized to 960 mg of vemurafenib orally twice a day or 1,000 mg/m² of dacarbazine by intravenous infusion every 3 weeks. A double-blind study would have been difficult but doable, Dr. Chapman said; the Food and Drug Administration made the decision to do BRIM-3 as an open label trial.

A larger study was planned, but a data safety monitoring board halted the trial in December after an interim analysis. Although the original protocol did not call for crossover of patients from the control group to active therapy, Dr. Chapman said crossover was allowed because of the striking advantage demonstrated by vemurafenib.

Following the extraordinarily early closing of the trial, median follow-up was only 3 months in the data reported as of the end of 2010. Median survival has not been reached in the patients treated with vemurafenib, Dr. Chapman said, but is typically less than 8 months with dacarbazine.

He expressed optimism that the advantage would hold up over time. The Kaplan Meier survival curve "tracks almost perfectly" with that presented at the same meeting by Dr. Antoni Ribas of the phase II BRIM-2 study, which had a median follow-up of 7 months and an overall response rate of 53%. In that study, Dr. Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported, median overall survival had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months.

Some patients in BRIM-3 had not been enrolled long enough to be assessed, Dr. Chapman said, adding that 7 of 32 patients in the initial phase I trial were still being treated.

Despite periods of remission that are long for metastatic melanoma, most patients eventually experience disease recurrence on vemurafenib. Despite the experience so far, the investigators are hoping that some patients will survive long-term, Dr. Chapman said.

The side effect profile was manageable, according to the investigators. Only about 10% of patients on active therapy had grade 3 or higher toxicity. Joint pain, photosensitivity, and skin rashes were the most common. About 20% of patients developed cutaneous squamous cell carcinoma, but it was benign and easily removed by dermatologists. Only 6% of patients on vemurafenib and 4% on dacarbazine discontinued because of adverse events.

The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find that 6 of 10 responded to vemurafenib, Dr. Chapman said in an interview. While more analysis is need, he was encouraged that it would be effective in these patients as well. Other studies are looking at efficacy in other malignancies such as thyroid cancer in which a subset of patients are known to have these mutations.

As for the pressing question of how and when to use vemurafenib in clinical practice, the quick action of vemurafenib in relieving symptom burden would make it the first choice in patients who have BRAF mutations and are very sick, according to Dr. Kim Allyson Margolin of the University of Washington Fred Hutchinson Cancer Research Center in Seattle.

In an invited discussion of BRIM-3 and the new ipilimumab data, she said rapid response is likely in patients treated with vemurafenib, and their tumor burden would be lower if they switched later to ipilimumab. Other subsequent therapies and combinations need to be explored, she said.

In contrast, Dr. Margolin suggested slower-working ipilimumab might be the first choice in patients with low tumor burden and minimal symptoms. If they progress, however, she would switch them to vemurafenib. "Both agents require experience and commitment by the M.D., and patient to management of unique toxicities," she advised.

As for the studies to come next, she cited single-agent questions about biomarkers of resistance, predictors of toxicity, and patient management issues. Among agents to be studied in combination with vemurafenib, she proposed MEK inhibitors, PI3K and mTOR inhibitors, IGFR inhibitors, immunomodulators, and cytotoxic agents.

Genentech sponsored the BRIM-2 and BRIM-3 trials. Dr. Chapman reported consultant/advisory roles and research funding from its parent company Roche. Some coauthors were Roche employees, and others reported similar relationships with Genentech. Dr. Ribas and several of his co-authors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Schuchter had no disclosures. Dr. Ernstoff made no relevant financial conflicts of interest.