Melanoma

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.

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.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18)), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics (Rheumatology News, May 2011, p. 1).

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a rheumatologist you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18)), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics (Rheumatology News, May 2011, p. 1).

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a rheumatologist you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18)), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics (Rheumatology News, May 2011, p. 1).

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a rheumatologist you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics.

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a [physician] you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics.

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a [physician] you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

LONDON – Biologic therapies do not increase the overall risk of cancer in patients with inflammatory arthritis, according to observational data from the Danish Biologics Register, DANBIO, presented by Dr. Lene Dreyer at the annual European Congress of Rheumatology.

After an average of 9 years of follow-up, and representing almost 24,000 patient-years of treatment, the relative risk (RR) for developing any type of cancer for the first time was 1.03 (95% confidence interval [CI] 0.82-1.30) when comparing anti–tumor necrosis factor (anti-TNF) therapy with no biologic treatment.

The cancer risk was also not increased in patients with rheumatoid arthritis (RR = 1.05; 95% CI 0.82-1.34), psoriatic arthritis (RR = 1.98; 95% CI 0.24-16.18), or other arthritic diseases including ankylosing spondylitis (RR = 0.79; 95% CI 0.08-8.33).

Preliminary results suggest that the risk of nonmelanoma skin cancer (RR = 1.11; 95% CI 0.70-1.76) and non-Hodgkin’s lymphoma are also not increased (RR = 0.55; 95% CI 0.16-1.90).

While the findings add to increasing evidence that biologics may not increase cancer risk overall, more analysis is needed to determine if certain types of cancer are more likely to occur in the study population, or if certain patients are at greater risk of malignancy than others. Longer follow-up is also needed to rule out cancers that may take longer than a decade to manifest.

"There has always been concern for an increased risk of lymphoma with TNF-blockers," said Dr. Georg Schett, chair of the department of internal medicine, rheumatology, and clinical immunology at Friedrich-Alexander University Erlangen in Nuremberg, Germany.

Dr. Schett, who was not involved in the study, added that patients with more active arthritis may be more likely than those with less active disease to receive anti-TNF treatment, and so these patients may already be at increased risk for lymphoma.

Indeed, recent data from the British Society for Rheumatology Biologics Register (BSRBR) have shown that the risk of cancer is almost doubled in patients with RA compared with the general population before they are even given biologics.

"There is an increased risk of cancer in patients with rheumatoid arthritis because of the disease itself," agreed study investigator Dr. Dreyer in an interview. In particular, there was an increased risk of lung cancer in Danish patients because of smoking, said Dr. Dreyer, who is a rheumatologist at Gentofte Hospital in Copenhagen.

Dr. Merete Lund Hetland, a consultant rheumatologist from Glostrup University Hospital in Copenhagen and chair of the Danish register, added in an interview: "I think as a [physician] you would always tell your patient, ‘Well, we don’t think there is an increased risk, but there’s always a risk, so you should tell us if you experience any signs or symptoms [that might indicate cancer].’ "

Putting the cancer risk in further context, Dr. Dreyer noted that the risk of infection was higher than that of malignancy, and that of course the benefits of biologic treatment would probably outweigh the risk of malignancy in the majority of patients.

DANBIO (Dansk Reumatologisk Database) was set up in 2000 to prospectively follow all patients starting treatment with anti-TNFs for their arthritis in Denmark. Enrollment in the register is mandatory and included more than 13,500 patients with all types of inflammatory arthritis up until the data cut for the analysis of 2008. Of the enrolled patients, 5,598 had received treatment with anti-TNF agents and 8,101 had not. Two-thirds of patients had rheumatoid arthritis.

To assess cancer risk, data from DANBIO were linked to the Danish Cancer Registry, with a total of 181 first cancers occurring in patients treated with biologics and 132 in those who were not given biologics.

The risk of cancer was the same for men and women, did not increase with the cumulative duration of active treatment, and was independent of the anti-TNF agent used (primarily infliximab, etanercept, and adalimumab).

Similar to other European biologics registers, DANBIO is funded by research grants from all the major players in the biologics market in Denmark. These grants run through the Danish Rheumatism Association and the Danish Cancer Society, and the sponsors have no direct access or influence on how the registry data are collected, analyzed, or published.

"All companies are involved. They all pay the same amount, and we would monitor all drugs regardless of whether there was a sponsor or not," Dr. Hetland said.

The DANBIO team plans to examine the association between biologic treatment and malignancy further, looking at the subtypes of cancer that develop. The team also plans to investigate in more detail the different types of cancer that develop by the type of arthritis.

DANBIO is financially supported by grants from the Danish Rheumatism Association and the Danish Cancer Society. Dr. Hetland has acted as a consultant to Roche, and has received grants and research support on behalf of DANBIO from Abbott, BMS, Centocor, Roche, Schering-Plough, UCB-Nordic, and Wyeth. Dr. Dreyer had no disclosures. Dr. Schett was not involved in the study.

Herbert C. Chiang, MD, PhD, Victor Huang, MD, and Lynn A. Cornelius, MD

Itch represents a common and significant source of morbidity in the oncological setting. Itch sometimes can be associated with an underlying malignancy, most commonly leukemia or lymphoma. Alternatively, itch may present secondary to malignant invasion causing hepatic or renal dysfunction. Finally, itch may be related to therapeutic regimens for the underlying malignancy. This article seeks to review the clinical scenarios in which itch affects the oncological patient, to briefly present the latest understanding of the molecular and cellular mechanisms of malignancy-related itch, and to review currently available therapeutic options.

*For a PDF of the full article, click on the link to the left of this introduction.

Herbert C. Chiang, MD, PhD, Victor Huang, MD, and Lynn A. Cornelius, MD

Itch represents a common and significant source of morbidity in the oncological setting. Itch sometimes can be associated with an underlying malignancy, most commonly leukemia or lymphoma. Alternatively, itch may present secondary to malignant invasion causing hepatic or renal dysfunction. Finally, itch may be related to therapeutic regimens for the underlying malignancy. This article seeks to review the clinical scenarios in which itch affects the oncological patient, to briefly present the latest understanding of the molecular and cellular mechanisms of malignancy-related itch, and to review currently available therapeutic options.

*For a PDF of the full article, click on the link to the left of this introduction.

Herbert C. Chiang, MD, PhD, Victor Huang, MD, and Lynn A. Cornelius, MD

Itch represents a common and significant source of morbidity in the oncological setting. Itch sometimes can be associated with an underlying malignancy, most commonly leukemia or lymphoma. Alternatively, itch may present secondary to malignant invasion causing hepatic or renal dysfunction. Finally, itch may be related to therapeutic regimens for the underlying malignancy. This article seeks to review the clinical scenarios in which itch affects the oncological patient, to briefly present the latest understanding of the molecular and cellular mechanisms of malignancy-related itch, and to review currently available therapeutic options.

*For a PDF of the full article, click on the link to the left of this introduction.

In this month's episode reporters discuss a possible cure for acne based on research being conducted by Dr. R. Rox Anderson.

Photo credit: Naseem Miller

Dr. Albert C. Yan goes head to head with lice. He talks about a regimen that uses Cetaphil to suffocate the bugs.

Tips for reducing infection rates during nail surgery are given by Dr. Nathaniel Jellinek.

Dr. Lily Talakoub talks all things sunscreen.

And, last but not least, Dr. Alan Rockoff closes this month's episode with a story about a patient with very strong opinions, and he does a little singing too.

In this month's episode reporters discuss a possible cure for acne based on research being conducted by Dr. R. Rox Anderson.

Photo credit: Naseem Miller

Dr. Albert C. Yan goes head to head with lice. He talks about a regimen that uses Cetaphil to suffocate the bugs.

Tips for reducing infection rates during nail surgery are given by Dr. Nathaniel Jellinek.

Dr. Lily Talakoub talks all things sunscreen.

And, last but not least, Dr. Alan Rockoff closes this month's episode with a story about a patient with very strong opinions, and he does a little singing too.

In this month's episode reporters discuss a possible cure for acne based on research being conducted by Dr. R. Rox Anderson.

Photo credit: Naseem Miller

Dr. Albert C. Yan goes head to head with lice. He talks about a regimen that uses Cetaphil to suffocate the bugs.

Tips for reducing infection rates during nail surgery are given by Dr. Nathaniel Jellinek.

Dr. Lily Talakoub talks all things sunscreen.

And, last but not least, Dr. Alan Rockoff closes this month's episode with a story about a patient with very strong opinions, and he does a little singing too.

GRAPEVINE, TEX. – The nonablative fractional thulium 1927-nm laser effectively treated actinic cheilitis in 15 patients, without subsequent downtime or significant side effects, Dr. Robert Anolik reported at the annual meeting of the American Society for Laser Medicine and Surgery.

Current treatments for actinic cheilitis – including surgery, carbon dioxide/erbium laser ablation, electrodesiccation, and 5-fluorouracil – typically involve significant pain, edema, and other adverse effects, including permanent scarring. The 1927-nm thulium laser, which is effective and well tolerated for superficial resurfacing, has been approved by the Food and Drug Administration for treating actinic keratoses, said Dr. Anolik of the Laser and Skin Surgery Center of New York.

Charts were reviewed for the 15 patients with actinic cheilitis who had been treated with the nonablative fractional 1,927-nm laser at two private laser and skin surgery centers. All were pretreated with topical anesthetic creams and given oral antiviral prophylaxis. Treatment parameters were 10-20 mJ per MTZ, 65%-70% coverage density, and total delivered energy of 0.08-0.1 kJ.

In blinded assessments of before and after photographs using a quartile improvement scale, all 15 patients had improvements of either 76%-100% (9 patients) or 51%-75% (6 patients) after 1-2 treatments. No adverse events occurred, and the only side effects were transient erythema for 1-4 days and edema for 1-3 days. "This is in stark contrast to the wounding, pain, and downtime expected with the other common treatment strategies," Dr. Anolik commented.

Planned next steps include increasing the patient pool, trial treatment of patients with a range of actinic cheilitis severity, assessment of before/after or left/right specimens for molecular features of actinic cheilitis such as p53, and an evaluation of long term benefit, he noted.

Dr. Anolik stated that he has no relevant relationships with industry.

GRAPEVINE, TEX. – The nonablative fractional thulium 1927-nm laser effectively treated actinic cheilitis in 15 patients, without subsequent downtime or significant side effects, Dr. Robert Anolik reported at the annual meeting of the American Society for Laser Medicine and Surgery.

Current treatments for actinic cheilitis – including surgery, carbon dioxide/erbium laser ablation, electrodesiccation, and 5-fluorouracil – typically involve significant pain, edema, and other adverse effects, including permanent scarring. The 1927-nm thulium laser, which is effective and well tolerated for superficial resurfacing, has been approved by the Food and Drug Administration for treating actinic keratoses, said Dr. Anolik of the Laser and Skin Surgery Center of New York.

Charts were reviewed for the 15 patients with actinic cheilitis who had been treated with the nonablative fractional 1,927-nm laser at two private laser and skin surgery centers. All were pretreated with topical anesthetic creams and given oral antiviral prophylaxis. Treatment parameters were 10-20 mJ per MTZ, 65%-70% coverage density, and total delivered energy of 0.08-0.1 kJ.

In blinded assessments of before and after photographs using a quartile improvement scale, all 15 patients had improvements of either 76%-100% (9 patients) or 51%-75% (6 patients) after 1-2 treatments. No adverse events occurred, and the only side effects were transient erythema for 1-4 days and edema for 1-3 days. "This is in stark contrast to the wounding, pain, and downtime expected with the other common treatment strategies," Dr. Anolik commented.

Planned next steps include increasing the patient pool, trial treatment of patients with a range of actinic cheilitis severity, assessment of before/after or left/right specimens for molecular features of actinic cheilitis such as p53, and an evaluation of long term benefit, he noted.

Dr. Anolik stated that he has no relevant relationships with industry.

GRAPEVINE, TEX. – The nonablative fractional thulium 1927-nm laser effectively treated actinic cheilitis in 15 patients, without subsequent downtime or significant side effects, Dr. Robert Anolik reported at the annual meeting of the American Society for Laser Medicine and Surgery.

Current treatments for actinic cheilitis – including surgery, carbon dioxide/erbium laser ablation, electrodesiccation, and 5-fluorouracil – typically involve significant pain, edema, and other adverse effects, including permanent scarring. The 1927-nm thulium laser, which is effective and well tolerated for superficial resurfacing, has been approved by the Food and Drug Administration for treating actinic keratoses, said Dr. Anolik of the Laser and Skin Surgery Center of New York.

Charts were reviewed for the 15 patients with actinic cheilitis who had been treated with the nonablative fractional 1,927-nm laser at two private laser and skin surgery centers. All were pretreated with topical anesthetic creams and given oral antiviral prophylaxis. Treatment parameters were 10-20 mJ per MTZ, 65%-70% coverage density, and total delivered energy of 0.08-0.1 kJ.

In blinded assessments of before and after photographs using a quartile improvement scale, all 15 patients had improvements of either 76%-100% (9 patients) or 51%-75% (6 patients) after 1-2 treatments. No adverse events occurred, and the only side effects were transient erythema for 1-4 days and edema for 1-3 days. "This is in stark contrast to the wounding, pain, and downtime expected with the other common treatment strategies," Dr. Anolik commented.

Planned next steps include increasing the patient pool, trial treatment of patients with a range of actinic cheilitis severity, assessment of before/after or left/right specimens for molecular features of actinic cheilitis such as p53, and an evaluation of long term benefit, he noted.

Dr. Anolik stated that he has no relevant relationships with industry.