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JAK Inhibitor Ruxolitinib Wins First FDA Approval in Myelofibrosis
In a much-anticipated double milestone, the Food and Drug Administration has approved ruxolitinib for treatment of patients with myelofibrosis.
Ruxolitinib, an orphan drug to be marketed as Jakafi by Incyte Corp., becomes the first agent to be approved for the rare blood disease. The indication covers patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, according to a statement from Wilmington, Del.–based Incyte.
The FDA decision also makes ruxolitinib the first approved agent in a new class of drugs called JAK (Janus-associated kinase) inhibitors. Deregulation of signaling in the JAK pathway is believed to be associated with the enlarged spleen and other symptoms of myelofibrosis. Ruxolitinib inhibits the tyrosine kinases JAK1 and JAK2, which are suspected of being up-regulated in various inflammatory disorders and malignancies.
"Jakafi represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.
"The clinical trials leading to this approval focused on problems that patients with myelofibrosis commonly encounter, including enlarged spleens and pain," he noted.
In the pivotal phase III COMFORT-I and COMFORT-II trials, ruxolitinib produced substantial symptom relief in patients who were resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All 528 patients in these studies had enlarged spleens (splenomegaly) and other disease-related symptoms. They were assigned to treatment with ruxolitinib, placebo, or best available therapy (usually hydroxyurea or glucocorticoids).
More patients on ruxolitinib had a greater-than-35% reduction in spleen size, compared with those given the alternatives, the FDA noted. Similarly, patients on ruxolitinib were more likely to have a more-than-50% reduction in MF-related symptoms, such as abdominal discomfort, night sweats, itching, and bone or muscle pain, compared with placebo.
The Incyte announcement noted that 41.9% of patients who were treated with ruxolitinib in the COMFORT-I trial had a 35% or greater reduction in spleen volume at 24 weeks, compared with 0.7% of patients taking placebo (P less than 0.0001). The median time to response was less than 4 weeks.
In the COMFORT-II trial, 28.5% of patients who were treated with ruxolitinib had a 35% or greater reduction in spleen volume at 48 weeks, compared with none of the patients in the best available therapy arm, Incyte said. COMFORT-II was conducted by Novartis, which is collaborating with Incyte outside the United States.
Incyte said that the ruxolitinib dosage should be adjusted based on safety and efficacy. The recommended starting dose of ruxolitinib for most patients of 15 mg or 20 mg given orally twice daily based on the patient’s platelet count. A blood cell count must be performed before initiation of therapy, the company said, and complete blood counts should be monitored every 2-4 weeks until doses are stabilized.
Thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea were the most common side effects, according to the FDA.
In a much-anticipated double milestone, the Food and Drug Administration has approved ruxolitinib for treatment of patients with myelofibrosis.
Ruxolitinib, an orphan drug to be marketed as Jakafi by Incyte Corp., becomes the first agent to be approved for the rare blood disease. The indication covers patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, according to a statement from Wilmington, Del.–based Incyte.
The FDA decision also makes ruxolitinib the first approved agent in a new class of drugs called JAK (Janus-associated kinase) inhibitors. Deregulation of signaling in the JAK pathway is believed to be associated with the enlarged spleen and other symptoms of myelofibrosis. Ruxolitinib inhibits the tyrosine kinases JAK1 and JAK2, which are suspected of being up-regulated in various inflammatory disorders and malignancies.
"Jakafi represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.
"The clinical trials leading to this approval focused on problems that patients with myelofibrosis commonly encounter, including enlarged spleens and pain," he noted.
In the pivotal phase III COMFORT-I and COMFORT-II trials, ruxolitinib produced substantial symptom relief in patients who were resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All 528 patients in these studies had enlarged spleens (splenomegaly) and other disease-related symptoms. They were assigned to treatment with ruxolitinib, placebo, or best available therapy (usually hydroxyurea or glucocorticoids).
More patients on ruxolitinib had a greater-than-35% reduction in spleen size, compared with those given the alternatives, the FDA noted. Similarly, patients on ruxolitinib were more likely to have a more-than-50% reduction in MF-related symptoms, such as abdominal discomfort, night sweats, itching, and bone or muscle pain, compared with placebo.
The Incyte announcement noted that 41.9% of patients who were treated with ruxolitinib in the COMFORT-I trial had a 35% or greater reduction in spleen volume at 24 weeks, compared with 0.7% of patients taking placebo (P less than 0.0001). The median time to response was less than 4 weeks.
In the COMFORT-II trial, 28.5% of patients who were treated with ruxolitinib had a 35% or greater reduction in spleen volume at 48 weeks, compared with none of the patients in the best available therapy arm, Incyte said. COMFORT-II was conducted by Novartis, which is collaborating with Incyte outside the United States.
Incyte said that the ruxolitinib dosage should be adjusted based on safety and efficacy. The recommended starting dose of ruxolitinib for most patients of 15 mg or 20 mg given orally twice daily based on the patient’s platelet count. A blood cell count must be performed before initiation of therapy, the company said, and complete blood counts should be monitored every 2-4 weeks until doses are stabilized.
Thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea were the most common side effects, according to the FDA.
In a much-anticipated double milestone, the Food and Drug Administration has approved ruxolitinib for treatment of patients with myelofibrosis.
Ruxolitinib, an orphan drug to be marketed as Jakafi by Incyte Corp., becomes the first agent to be approved for the rare blood disease. The indication covers patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, according to a statement from Wilmington, Del.–based Incyte.
The FDA decision also makes ruxolitinib the first approved agent in a new class of drugs called JAK (Janus-associated kinase) inhibitors. Deregulation of signaling in the JAK pathway is believed to be associated with the enlarged spleen and other symptoms of myelofibrosis. Ruxolitinib inhibits the tyrosine kinases JAK1 and JAK2, which are suspected of being up-regulated in various inflammatory disorders and malignancies.
"Jakafi represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the agency’s announcement.
"The clinical trials leading to this approval focused on problems that patients with myelofibrosis commonly encounter, including enlarged spleens and pain," he noted.
In the pivotal phase III COMFORT-I and COMFORT-II trials, ruxolitinib produced substantial symptom relief in patients who were resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All 528 patients in these studies had enlarged spleens (splenomegaly) and other disease-related symptoms. They were assigned to treatment with ruxolitinib, placebo, or best available therapy (usually hydroxyurea or glucocorticoids).
More patients on ruxolitinib had a greater-than-35% reduction in spleen size, compared with those given the alternatives, the FDA noted. Similarly, patients on ruxolitinib were more likely to have a more-than-50% reduction in MF-related symptoms, such as abdominal discomfort, night sweats, itching, and bone or muscle pain, compared with placebo.
The Incyte announcement noted that 41.9% of patients who were treated with ruxolitinib in the COMFORT-I trial had a 35% or greater reduction in spleen volume at 24 weeks, compared with 0.7% of patients taking placebo (P less than 0.0001). The median time to response was less than 4 weeks.
In the COMFORT-II trial, 28.5% of patients who were treated with ruxolitinib had a 35% or greater reduction in spleen volume at 48 weeks, compared with none of the patients in the best available therapy arm, Incyte said. COMFORT-II was conducted by Novartis, which is collaborating with Incyte outside the United States.
Incyte said that the ruxolitinib dosage should be adjusted based on safety and efficacy. The recommended starting dose of ruxolitinib for most patients of 15 mg or 20 mg given orally twice daily based on the patient’s platelet count. A blood cell count must be performed before initiation of therapy, the company said, and complete blood counts should be monitored every 2-4 weeks until doses are stabilized.
Thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea were the most common side effects, according to the FDA.
FDA Approves Deferiprone for Transfusional Iron Overload
Deferiprone is approved as a second-line treatment for transfusional iron overload when the condition has not been resolved by chelation therapy in patients with thalassemia, the Food and Drug Administration announced Oct. 14.
The new agent will be marketed as Ferriprox by ApoPharma. The FDA said the Toronto-based company has agreed to several postmarketing requirements and commitments, including further study in patients who have transfusional iron overload after treatment for sickle cell disease.
The FDA’s Oncologic Drugs Advisory Committee recently voted 10-2 that treatment with deferiprone had a favorable benefit-risk profile for treatment of patients with transfusional iron overload when current chelation therapy is inadequate.
As the decision date approached, however, the consumer advocacy group Public Citizen announced that it had sent the FDA a letter opposing approval. Public Citizen contended that APO Pharma had failed to demonstrate the drug is safe and effective in its intended population. The group noted that the FDA had refused to approve deferiprone in 2009 without an additional prospective, randomized, controlled study, but that no such study had been conducted.
"Ferriprox represents the first new FDA-approved treatment for this disorder since 2005."
The FDA announcement said its decision on safety and effectiveness was based on 12 clinical studies in which participating patients had not responded to prior iron chelation therapy.
"Ferriprox was considered a successful treatment for patients who experienced at least a 20% decrease in serum ferritin, a protein that stores iron in the body for later use. Half of the patients in the study experienced at least a 20% decrease in ferritin levels," the agency said.
Thalassemia is a genetic blood disorder that causes anemia. It is treated with frequent blood transfusions, but these can lead to excess iron in the body, a serious, potentially fatal condition. Chelation therapy, a process in which chemical agents remove heavy metals from the body, is the standard of care for transfusional iron overload.
"Ferriprox represents the first new FDA-approved treatment for this disorder since 2005," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA announcement.
Deferoxamine (Desferal), an iron chelator administered via a subcutaneous infusion pump (usually 6 nights a week), was approved in 1968, and deferasirox (Exjade), an oral chelator, in 2005. The new agent was approved in Europe in 1999, but had not been able to secure a U.S. go-ahead until the current "accelerated approval."
Ferriprox’s most common side effects have included nausea, vomiting, abdominal and joint pain, chromaturia, neutropenia, and "an increase in the level of a liver enzyme that may be indicative of tissue or liver damage at unsafe amounts," according to the FDA.
The agency said the most serious side effect was the development of agranulocytosis in about 2% of patients treated with Ferriprox.
Deferiprone is approved as a second-line treatment for transfusional iron overload when the condition has not been resolved by chelation therapy in patients with thalassemia, the Food and Drug Administration announced Oct. 14.
The new agent will be marketed as Ferriprox by ApoPharma. The FDA said the Toronto-based company has agreed to several postmarketing requirements and commitments, including further study in patients who have transfusional iron overload after treatment for sickle cell disease.
The FDA’s Oncologic Drugs Advisory Committee recently voted 10-2 that treatment with deferiprone had a favorable benefit-risk profile for treatment of patients with transfusional iron overload when current chelation therapy is inadequate.
As the decision date approached, however, the consumer advocacy group Public Citizen announced that it had sent the FDA a letter opposing approval. Public Citizen contended that APO Pharma had failed to demonstrate the drug is safe and effective in its intended population. The group noted that the FDA had refused to approve deferiprone in 2009 without an additional prospective, randomized, controlled study, but that no such study had been conducted.
"Ferriprox represents the first new FDA-approved treatment for this disorder since 2005."
The FDA announcement said its decision on safety and effectiveness was based on 12 clinical studies in which participating patients had not responded to prior iron chelation therapy.
"Ferriprox was considered a successful treatment for patients who experienced at least a 20% decrease in serum ferritin, a protein that stores iron in the body for later use. Half of the patients in the study experienced at least a 20% decrease in ferritin levels," the agency said.
Thalassemia is a genetic blood disorder that causes anemia. It is treated with frequent blood transfusions, but these can lead to excess iron in the body, a serious, potentially fatal condition. Chelation therapy, a process in which chemical agents remove heavy metals from the body, is the standard of care for transfusional iron overload.
"Ferriprox represents the first new FDA-approved treatment for this disorder since 2005," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA announcement.
Deferoxamine (Desferal), an iron chelator administered via a subcutaneous infusion pump (usually 6 nights a week), was approved in 1968, and deferasirox (Exjade), an oral chelator, in 2005. The new agent was approved in Europe in 1999, but had not been able to secure a U.S. go-ahead until the current "accelerated approval."
Ferriprox’s most common side effects have included nausea, vomiting, abdominal and joint pain, chromaturia, neutropenia, and "an increase in the level of a liver enzyme that may be indicative of tissue or liver damage at unsafe amounts," according to the FDA.
The agency said the most serious side effect was the development of agranulocytosis in about 2% of patients treated with Ferriprox.
Deferiprone is approved as a second-line treatment for transfusional iron overload when the condition has not been resolved by chelation therapy in patients with thalassemia, the Food and Drug Administration announced Oct. 14.
The new agent will be marketed as Ferriprox by ApoPharma. The FDA said the Toronto-based company has agreed to several postmarketing requirements and commitments, including further study in patients who have transfusional iron overload after treatment for sickle cell disease.
The FDA’s Oncologic Drugs Advisory Committee recently voted 10-2 that treatment with deferiprone had a favorable benefit-risk profile for treatment of patients with transfusional iron overload when current chelation therapy is inadequate.
As the decision date approached, however, the consumer advocacy group Public Citizen announced that it had sent the FDA a letter opposing approval. Public Citizen contended that APO Pharma had failed to demonstrate the drug is safe and effective in its intended population. The group noted that the FDA had refused to approve deferiprone in 2009 without an additional prospective, randomized, controlled study, but that no such study had been conducted.
"Ferriprox represents the first new FDA-approved treatment for this disorder since 2005."
The FDA announcement said its decision on safety and effectiveness was based on 12 clinical studies in which participating patients had not responded to prior iron chelation therapy.
"Ferriprox was considered a successful treatment for patients who experienced at least a 20% decrease in serum ferritin, a protein that stores iron in the body for later use. Half of the patients in the study experienced at least a 20% decrease in ferritin levels," the agency said.
Thalassemia is a genetic blood disorder that causes anemia. It is treated with frequent blood transfusions, but these can lead to excess iron in the body, a serious, potentially fatal condition. Chelation therapy, a process in which chemical agents remove heavy metals from the body, is the standard of care for transfusional iron overload.
"Ferriprox represents the first new FDA-approved treatment for this disorder since 2005," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA announcement.
Deferoxamine (Desferal), an iron chelator administered via a subcutaneous infusion pump (usually 6 nights a week), was approved in 1968, and deferasirox (Exjade), an oral chelator, in 2005. The new agent was approved in Europe in 1999, but had not been able to secure a U.S. go-ahead until the current "accelerated approval."
Ferriprox’s most common side effects have included nausea, vomiting, abdominal and joint pain, chromaturia, neutropenia, and "an increase in the level of a liver enzyme that may be indicative of tissue or liver damage at unsafe amounts," according to the FDA.
The agency said the most serious side effect was the development of agranulocytosis in about 2% of patients treated with Ferriprox.
FDA Approves Vemurafenib for Advanced Melanoma
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients.
The agency also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine if a patient’s melanoma cells carry the BRAF V600E mutation.
Vemurafenib is the second therapy to prolong the lives of patients with metastatic melanoma. The first, a slow-acting immunotherapy called ipilimumab (Yervoy), was approved in March 2011.
Clinical trials have shown that vemurafenib (better known as PLX4032) can produce rapid remission in patients at risk of death from metastatic melanoma.
Vemurafenib is not a panacea, as only about half of patients with BRAF V600E mutations have responded, and in the early studies almost all eventually relapsed. However, the drug has produced delays in recurrence and prolongations of overall survival that are clinically and statistically significant.
"This is a bright day for many melanoma patients," Dr. Jeffrey A. Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville said in response to the FDA announcement.
"But it is only the start, and we have to continue to enroll patients onto clinical trials in order to build upon this exciting advance. It is only the beginning," added Dr. Sosman, an investigator in the BRIM-3 trial that led to approval of vemurafenib.
Early results of the pivotal phase III BRIM-3 trial, presented at the American Society of Clinical Oncology (ASCO) in June, and published simultaneously in the New England Journal of Medicine (2011;364:2507-16) , showed that vemurafenib reduced the relative risk of death by 63% in comparison with dacarbazine (DTIC), a standard but ineffective therapy, at a median follow-up of 3 months.
The randomized, open-label study screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47% of patients. It accrued 675 patients from January 2010 though December 2010, but some had not been in the study long enough to be included in the reports, as the trial was stopped based on early positive results.
Among the findings were estimates that 84% of patients treated with oral vemurafenib but only 64% of those given DTIC would be alive at 6 months. Vemurafenib’s hazard ratio for death was 0.37 (P less than .0001). 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 versus 1.6 months with DTIC, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York City and colleagues reported. Median overall survival had not been reached in the vemurafenib arm of BRIM-3, but Dr. Chapman expressed optimism that the advantage would hold up over time, as the Kaplan Meier survival curve mirrored results from the precursor BRIM-2 trial.
In that phase II study, median overall survival also had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months, Dr. Antoni Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported at the ASCO meeting. His presentation was based on a median follow-up of 7 months with an overall response rate of 53%.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find about half responded to vemurafenib, Dr. Chapman said in an interview.
In yet another presentation at ASCO, Dr. Alexander M. Menzies of the Melanoma Institute Australia reported that BRAF mutations are more common in younger melanoma patients. In all, 46% of 311 advanced melanoma patients had a BRAF mutation; 73% of these were V600E mutations, 19% V600K, and the remainder other forms.
The mutation rate declined from more than 80% of melanoma patients aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years, Dr. Menzies said. The V600E mutation predominated in younger patients, occurring in 86% of those aged 20-30 years, whereas the V600K mutation emerged in older age.
Vemurafenib - approved at a recommended dose of 960 mg orally twice daily - has a manageable side effect profile, according to the BRIM-3 investigators. Although the safety data were not formally pooled, investigators said less than 10% of patients on active therapy had a 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 easily removed by dermatologists, and there were no instances of metastases. Only 6% of patients on vemurafenib discontinued because of adverse events.
Vemurafenib will be marketed as Zelboraf by Roche, which announced submission of applications for approval in the United States and Europe on May 11. Roche’s Genentech has a comarketing agreement with vemurafenib developer Plexxikon, a member of Daiichi Sankyo.
In June, Roche and Bristol-Meyers Squibb (maker of ipilimumab), announced that they would collaborate on a phase I/II study to determine whether combining the two drugs is safe and effective in patients with BRAF mutations.
The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.
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 coauthors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Menzies had no relevant financial conflicts of interest.
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients.
The agency also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine if a patient’s melanoma cells carry the BRAF V600E mutation.
Vemurafenib is the second therapy to prolong the lives of patients with metastatic melanoma. The first, a slow-acting immunotherapy called ipilimumab (Yervoy), was approved in March 2011.
Clinical trials have shown that vemurafenib (better known as PLX4032) can produce rapid remission in patients at risk of death from metastatic melanoma.
Vemurafenib is not a panacea, as only about half of patients with BRAF V600E mutations have responded, and in the early studies almost all eventually relapsed. However, the drug has produced delays in recurrence and prolongations of overall survival that are clinically and statistically significant.
"This is a bright day for many melanoma patients," Dr. Jeffrey A. Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville said in response to the FDA announcement.
"But it is only the start, and we have to continue to enroll patients onto clinical trials in order to build upon this exciting advance. It is only the beginning," added Dr. Sosman, an investigator in the BRIM-3 trial that led to approval of vemurafenib.
Early results of the pivotal phase III BRIM-3 trial, presented at the American Society of Clinical Oncology (ASCO) in June, and published simultaneously in the New England Journal of Medicine (2011;364:2507-16) , showed that vemurafenib reduced the relative risk of death by 63% in comparison with dacarbazine (DTIC), a standard but ineffective therapy, at a median follow-up of 3 months.
The randomized, open-label study screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47% of patients. It accrued 675 patients from January 2010 though December 2010, but some had not been in the study long enough to be included in the reports, as the trial was stopped based on early positive results.
Among the findings were estimates that 84% of patients treated with oral vemurafenib but only 64% of those given DTIC would be alive at 6 months. Vemurafenib’s hazard ratio for death was 0.37 (P less than .0001). 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 versus 1.6 months with DTIC, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York City and colleagues reported. Median overall survival had not been reached in the vemurafenib arm of BRIM-3, but Dr. Chapman expressed optimism that the advantage would hold up over time, as the Kaplan Meier survival curve mirrored results from the precursor BRIM-2 trial.
In that phase II study, median overall survival also had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months, Dr. Antoni Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported at the ASCO meeting. His presentation was based on a median follow-up of 7 months with an overall response rate of 53%.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find about half responded to vemurafenib, Dr. Chapman said in an interview.
In yet another presentation at ASCO, Dr. Alexander M. Menzies of the Melanoma Institute Australia reported that BRAF mutations are more common in younger melanoma patients. In all, 46% of 311 advanced melanoma patients had a BRAF mutation; 73% of these were V600E mutations, 19% V600K, and the remainder other forms.
The mutation rate declined from more than 80% of melanoma patients aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years, Dr. Menzies said. The V600E mutation predominated in younger patients, occurring in 86% of those aged 20-30 years, whereas the V600K mutation emerged in older age.
Vemurafenib - approved at a recommended dose of 960 mg orally twice daily - has a manageable side effect profile, according to the BRIM-3 investigators. Although the safety data were not formally pooled, investigators said less than 10% of patients on active therapy had a 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 easily removed by dermatologists, and there were no instances of metastases. Only 6% of patients on vemurafenib discontinued because of adverse events.
Vemurafenib will be marketed as Zelboraf by Roche, which announced submission of applications for approval in the United States and Europe on May 11. Roche’s Genentech has a comarketing agreement with vemurafenib developer Plexxikon, a member of Daiichi Sankyo.
In June, Roche and Bristol-Meyers Squibb (maker of ipilimumab), announced that they would collaborate on a phase I/II study to determine whether combining the two drugs is safe and effective in patients with BRAF mutations.
The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.
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 coauthors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Menzies had no relevant financial conflicts of interest.
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients.
The agency also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine if a patient’s melanoma cells carry the BRAF V600E mutation.
Vemurafenib is the second therapy to prolong the lives of patients with metastatic melanoma. The first, a slow-acting immunotherapy called ipilimumab (Yervoy), was approved in March 2011.
Clinical trials have shown that vemurafenib (better known as PLX4032) can produce rapid remission in patients at risk of death from metastatic melanoma.
Vemurafenib is not a panacea, as only about half of patients with BRAF V600E mutations have responded, and in the early studies almost all eventually relapsed. However, the drug has produced delays in recurrence and prolongations of overall survival that are clinically and statistically significant.
"This is a bright day for many melanoma patients," Dr. Jeffrey A. Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville said in response to the FDA announcement.
"But it is only the start, and we have to continue to enroll patients onto clinical trials in order to build upon this exciting advance. It is only the beginning," added Dr. Sosman, an investigator in the BRIM-3 trial that led to approval of vemurafenib.
Early results of the pivotal phase III BRIM-3 trial, presented at the American Society of Clinical Oncology (ASCO) in June, and published simultaneously in the New England Journal of Medicine (2011;364:2507-16) , showed that vemurafenib reduced the relative risk of death by 63% in comparison with dacarbazine (DTIC), a standard but ineffective therapy, at a median follow-up of 3 months.
The randomized, open-label study screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47% of patients. It accrued 675 patients from January 2010 though December 2010, but some had not been in the study long enough to be included in the reports, as the trial was stopped based on early positive results.
Among the findings were estimates that 84% of patients treated with oral vemurafenib but only 64% of those given DTIC would be alive at 6 months. Vemurafenib’s hazard ratio for death was 0.37 (P less than .0001). 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 versus 1.6 months with DTIC, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York City and colleagues reported. Median overall survival had not been reached in the vemurafenib arm of BRIM-3, but Dr. Chapman expressed optimism that the advantage would hold up over time, as the Kaplan Meier survival curve mirrored results from the precursor BRIM-2 trial.
In that phase II study, median overall survival also had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months, Dr. Antoni Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported at the ASCO meeting. His presentation was based on a median follow-up of 7 months with an overall response rate of 53%.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find about half responded to vemurafenib, Dr. Chapman said in an interview.
In yet another presentation at ASCO, Dr. Alexander M. Menzies of the Melanoma Institute Australia reported that BRAF mutations are more common in younger melanoma patients. In all, 46% of 311 advanced melanoma patients had a BRAF mutation; 73% of these were V600E mutations, 19% V600K, and the remainder other forms.
The mutation rate declined from more than 80% of melanoma patients aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years, Dr. Menzies said. The V600E mutation predominated in younger patients, occurring in 86% of those aged 20-30 years, whereas the V600K mutation emerged in older age.
Vemurafenib - approved at a recommended dose of 960 mg orally twice daily - has a manageable side effect profile, according to the BRIM-3 investigators. Although the safety data were not formally pooled, investigators said less than 10% of patients on active therapy had a 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 easily removed by dermatologists, and there were no instances of metastases. Only 6% of patients on vemurafenib discontinued because of adverse events.
Vemurafenib will be marketed as Zelboraf by Roche, which announced submission of applications for approval in the United States and Europe on May 11. Roche’s Genentech has a comarketing agreement with vemurafenib developer Plexxikon, a member of Daiichi Sankyo.
In June, Roche and Bristol-Meyers Squibb (maker of ipilimumab), announced that they would collaborate on a phase I/II study to determine whether combining the two drugs is safe and effective in patients with BRAF mutations.
The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.
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 coauthors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Menzies had no relevant financial conflicts of interest.
FDA Approves Vemurafenib for Advanced Melanoma
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients.
The agency also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine if a patient’s melanoma cells carry the BRAF V600E mutation.
Vemurafenib is the second therapy to prolong the lives of patients with metastatic melanoma. The first, a slow-acting immunotherapy called ipilimumab (Yervoy), was approved in March 2011.
Clinical trials have shown that vemurafenib (better known as PLX4032) can produce rapid remission in patients at risk of death from metastatic melanoma.
Vemurafenib is not a panacea, as only about half of patients with BRAF V600E mutations have responded, and in the early studies almost all eventually relapsed. However, the drug has produced delays in recurrence and prolongations of overall survival that are clinically and statistically significant.
"This is a bright day for many melanoma patients," Dr. Jeffrey A. Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville said in response to the FDA announcement.
"But it is only the start, and we have to continue to enroll patients onto clinical trials in order to build upon this exciting advance. It is only the beginning," added Dr. Sosman, an investigator in the BRIM-3 trial that led to approval of vemurafenib.
Early results of the pivotal phase III BRIM-3 trial, presented at the American Society of Clinical Oncology (ASCO) in June, and published simultaneously in the New England Journal of Medicine (2011;364:2507-16) , showed that vemurafenib reduced the relative risk of death by 63% in comparison with dacarbazine (DTIC), a standard but ineffective therapy, at a median follow-up of 3 months.
The randomized, open-label study screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47% of patients. It accrued 675 patients from January 2010 though December 2010, but some had not been in the study long enough to be included in the reports, as the trial was stopped based on early positive results.
Among the findings were estimates that 84% of patients treated with oral vemurafenib but only 64% of those given DTIC would be alive at 6 months. Vemurafenib’s hazard ratio for death was 0.37 (P less than .0001). 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 versus 1.6 months with DTIC, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York City and colleagues reported. Median overall survival had not been reached in the vemurafenib arm of BRIM-3, but Dr. Chapman expressed optimism that the advantage would hold up over time, as the Kaplan Meier survival curve mirrored results from the precursor BRIM-2 trial.
In that phase II study, median overall survival also had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months, Dr. Antoni Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported at the ASCO meeting. His presentation was based on a median follow-up of 7 months with an overall response rate of 53%.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find about half responded to vemurafenib, Dr. Chapman said in an interview.
In yet another presentation at ASCO, Dr. Alexander M. Menzies of the Melanoma Institute Australia reported that BRAF mutations are more common in younger melanoma patients. In all, 46% of 311 advanced melanoma patients had a BRAF mutation; 73% of these were V600E mutations, 19% V600K, and the remainder other forms.
The mutation rate declined from more than 80% of melanoma patients aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years, Dr. Menzies said. The V600E mutation predominated in younger patients, occurring in 86% of those aged 20-30 years, whereas the V600K mutation emerged in older age.
Vemurafenib - approved at a recommended dose of 960 mg orally twice daily - has a manageable side effect profile, according to the BRIM-3 investigators. Although the safety data were not formally pooled, investigators said less than 10% of patients on active therapy had a 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 easily removed by dermatologists, and there were no instances of metastases. Only 6% of patients on vemurafenib discontinued because of adverse events.
Vemurafenib will be marketed as Zelboraf by Roche, which announced submission of applications for approval in the United States and Europe on May 11. Roche’s Genentech has a comarketing agreement with vemurafenib developer Plexxikon, a member of Daiichi Sankyo.
In June, Roche and Bristol-Meyers Squibb (maker of ipilimumab), announced that they would collaborate on a phase I/II study to determine whether combining the two drugs is safe and effective in patients with BRAF mutations.
The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.
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 coauthors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Menzies had no relevant financial conflicts of interest.
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients.
The agency also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine if a patient’s melanoma cells carry the BRAF V600E mutation.
Vemurafenib is the second therapy to prolong the lives of patients with metastatic melanoma. The first, a slow-acting immunotherapy called ipilimumab (Yervoy), was approved in March 2011.
Clinical trials have shown that vemurafenib (better known as PLX4032) can produce rapid remission in patients at risk of death from metastatic melanoma.
Vemurafenib is not a panacea, as only about half of patients with BRAF V600E mutations have responded, and in the early studies almost all eventually relapsed. However, the drug has produced delays in recurrence and prolongations of overall survival that are clinically and statistically significant.
"This is a bright day for many melanoma patients," Dr. Jeffrey A. Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville said in response to the FDA announcement.
"But it is only the start, and we have to continue to enroll patients onto clinical trials in order to build upon this exciting advance. It is only the beginning," added Dr. Sosman, an investigator in the BRIM-3 trial that led to approval of vemurafenib.
Early results of the pivotal phase III BRIM-3 trial, presented at the American Society of Clinical Oncology (ASCO) in June, and published simultaneously in the New England Journal of Medicine (2011;364:2507-16) , showed that vemurafenib reduced the relative risk of death by 63% in comparison with dacarbazine (DTIC), a standard but ineffective therapy, at a median follow-up of 3 months.
The randomized, open-label study screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47% of patients. It accrued 675 patients from January 2010 though December 2010, but some had not been in the study long enough to be included in the reports, as the trial was stopped based on early positive results.
Among the findings were estimates that 84% of patients treated with oral vemurafenib but only 64% of those given DTIC would be alive at 6 months. Vemurafenib’s hazard ratio for death was 0.37 (P less than .0001). 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 versus 1.6 months with DTIC, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York City and colleagues reported. Median overall survival had not been reached in the vemurafenib arm of BRIM-3, but Dr. Chapman expressed optimism that the advantage would hold up over time, as the Kaplan Meier survival curve mirrored results from the precursor BRIM-2 trial.
In that phase II study, median overall survival also had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months, Dr. Antoni Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported at the ASCO meeting. His presentation was based on a median follow-up of 7 months with an overall response rate of 53%.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find about half responded to vemurafenib, Dr. Chapman said in an interview.
In yet another presentation at ASCO, Dr. Alexander M. Menzies of the Melanoma Institute Australia reported that BRAF mutations are more common in younger melanoma patients. In all, 46% of 311 advanced melanoma patients had a BRAF mutation; 73% of these were V600E mutations, 19% V600K, and the remainder other forms.
The mutation rate declined from more than 80% of melanoma patients aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years, Dr. Menzies said. The V600E mutation predominated in younger patients, occurring in 86% of those aged 20-30 years, whereas the V600K mutation emerged in older age.
Vemurafenib - approved at a recommended dose of 960 mg orally twice daily - has a manageable side effect profile, according to the BRIM-3 investigators. Although the safety data were not formally pooled, investigators said less than 10% of patients on active therapy had a 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 easily removed by dermatologists, and there were no instances of metastases. Only 6% of patients on vemurafenib discontinued because of adverse events.
Vemurafenib will be marketed as Zelboraf by Roche, which announced submission of applications for approval in the United States and Europe on May 11. Roche’s Genentech has a comarketing agreement with vemurafenib developer Plexxikon, a member of Daiichi Sankyo.
In June, Roche and Bristol-Meyers Squibb (maker of ipilimumab), announced that they would collaborate on a phase I/II study to determine whether combining the two drugs is safe and effective in patients with BRAF mutations.
The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.
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 coauthors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Menzies had no relevant financial conflicts of interest.
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients.
The agency also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine if a patient’s melanoma cells carry the BRAF V600E mutation.
Vemurafenib is the second therapy to prolong the lives of patients with metastatic melanoma. The first, a slow-acting immunotherapy called ipilimumab (Yervoy), was approved in March 2011.
Clinical trials have shown that vemurafenib (better known as PLX4032) can produce rapid remission in patients at risk of death from metastatic melanoma.
Vemurafenib is not a panacea, as only about half of patients with BRAF V600E mutations have responded, and in the early studies almost all eventually relapsed. However, the drug has produced delays in recurrence and prolongations of overall survival that are clinically and statistically significant.
"This is a bright day for many melanoma patients," Dr. Jeffrey A. Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville said in response to the FDA announcement.
"But it is only the start, and we have to continue to enroll patients onto clinical trials in order to build upon this exciting advance. It is only the beginning," added Dr. Sosman, an investigator in the BRIM-3 trial that led to approval of vemurafenib.
Early results of the pivotal phase III BRIM-3 trial, presented at the American Society of Clinical Oncology (ASCO) in June, and published simultaneously in the New England Journal of Medicine (2011;364:2507-16) , showed that vemurafenib reduced the relative risk of death by 63% in comparison with dacarbazine (DTIC), a standard but ineffective therapy, at a median follow-up of 3 months.
The randomized, open-label study screened 2,107 patients with unresectable stage III or IV melanoma for BRAF mutations, which were found in 47% of patients. It accrued 675 patients from January 2010 though December 2010, but some had not been in the study long enough to be included in the reports, as the trial was stopped based on early positive results.
Among the findings were estimates that 84% of patients treated with oral vemurafenib but only 64% of those given DTIC would be alive at 6 months. Vemurafenib’s hazard ratio for death was 0.37 (P less than .0001). 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 versus 1.6 months with DTIC, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York City and colleagues reported. Median overall survival had not been reached in the vemurafenib arm of BRIM-3, but Dr. Chapman expressed optimism that the advantage would hold up over time, as the Kaplan Meier survival curve mirrored results from the precursor BRIM-2 trial.
In that phase II study, median overall survival also had not yet been reached with 77% of patients alive at 6 months and 58% at 12 months, Dr. Antoni Ribas of the Jonsson Comprehensive Cancer Center in Los Angeles reported at the ASCO meeting. His presentation was based on a median follow-up of 7 months with an overall response rate of 53%.
The investigators also looked at patients who had BRAF mutations other than V600E, and were encouraged to find about half responded to vemurafenib, Dr. Chapman said in an interview.
In yet another presentation at ASCO, Dr. Alexander M. Menzies of the Melanoma Institute Australia reported that BRAF mutations are more common in younger melanoma patients. In all, 46% of 311 advanced melanoma patients had a BRAF mutation; 73% of these were V600E mutations, 19% V600K, and the remainder other forms.
The mutation rate declined from more than 80% of melanoma patients aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years, Dr. Menzies said. The V600E mutation predominated in younger patients, occurring in 86% of those aged 20-30 years, whereas the V600K mutation emerged in older age.
Vemurafenib - approved at a recommended dose of 960 mg orally twice daily - has a manageable side effect profile, according to the BRIM-3 investigators. Although the safety data were not formally pooled, investigators said less than 10% of patients on active therapy had a 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 easily removed by dermatologists, and there were no instances of metastases. Only 6% of patients on vemurafenib discontinued because of adverse events.
Vemurafenib will be marketed as Zelboraf by Roche, which announced submission of applications for approval in the United States and Europe on May 11. Roche’s Genentech has a comarketing agreement with vemurafenib developer Plexxikon, a member of Daiichi Sankyo.
In June, Roche and Bristol-Meyers Squibb (maker of ipilimumab), announced that they would collaborate on a phase I/II study to determine whether combining the two drugs is safe and effective in patients with BRAF mutations.
The cobas 4800 BRAF V600 Mutation Test is manufactured by Roche Molecular Systems in Pleasanton, Calif.
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 coauthors reported similar consulting and advisory relationships with Roche/Genentech. Dr. Menzies had no relevant financial conflicts of interest.
Q&A: Putting the New Melanoma Drugs to Work
For the first time, physicians have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into practice. We asked four experts for their thoughts on what comes next:
• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.
• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.
• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.
• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.
Question: Should ipilimumab and vemurafenib be used together?
Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.
Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.
I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before physicians begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.
Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren’t what you expect. Don’t just take a patient and give them both and see what happens. That’s not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.
Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.
Question: So which agent would you use first in a patient who has a BRAF mutation?
Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.
Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.
The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can’t have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies - the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn’t work, I think vemurafenib.
Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. ... All BRAF-negative patients would see ipilimumab in first line. That is for sure.
Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?
Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don’t have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.
There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.
Question: Will interleukin-2 still have a role in melanoma treatment?
Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. ... We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don’t know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.
Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down... If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it’s not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.
Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients ... and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.
Question: And interferon – Where will it fit in?
Dr. Sondak: We don’t know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn’t sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.
It’s very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.
In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn’t very sturdy to walk on, but we’re trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It’s real exciting – not just the data we already have but for the future and how many patients this will affect positively.
Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.
For the first time, physicians have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into practice. We asked four experts for their thoughts on what comes next:
• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.
• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.
• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.
• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.
Question: Should ipilimumab and vemurafenib be used together?
Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.
Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.
I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before physicians begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.
Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren’t what you expect. Don’t just take a patient and give them both and see what happens. That’s not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.
Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.
Question: So which agent would you use first in a patient who has a BRAF mutation?
Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.
Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.
The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can’t have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies - the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn’t work, I think vemurafenib.
Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. ... All BRAF-negative patients would see ipilimumab in first line. That is for sure.
Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?
Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don’t have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.
There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.
Question: Will interleukin-2 still have a role in melanoma treatment?
Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. ... We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don’t know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.
Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down... If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it’s not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.
Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients ... and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.
Question: And interferon – Where will it fit in?
Dr. Sondak: We don’t know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn’t sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.
It’s very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.
In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn’t very sturdy to walk on, but we’re trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It’s real exciting – not just the data we already have but for the future and how many patients this will affect positively.
Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.
For the first time, physicians have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into practice. We asked four experts for their thoughts on what comes next:
• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.
• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.
• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.
• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.
Question: Should ipilimumab and vemurafenib be used together?
Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.
Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.
I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before physicians begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.
Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren’t what you expect. Don’t just take a patient and give them both and see what happens. That’s not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.
Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.
Question: So which agent would you use first in a patient who has a BRAF mutation?
Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.
Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.
The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can’t have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies - the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn’t work, I think vemurafenib.
Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. ... All BRAF-negative patients would see ipilimumab in first line. That is for sure.
Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?
Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don’t have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.
There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.
Question: Will interleukin-2 still have a role in melanoma treatment?
Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. ... We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don’t know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.
Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down... If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it’s not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.
Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients ... and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.
Question: And interferon – Where will it fit in?
Dr. Sondak: We don’t know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn’t sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.
It’s very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.
In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn’t very sturdy to walk on, but we’re trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It’s real exciting – not just the data we already have but for the future and how many patients this will affect positively.
Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Q&A: Putting New Melanoma Drugs to Work in Community Practice
Euphoria – there is no better word to describe the mood in the melanoma sessions at ASCO. For the first time ever, oncologists have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into community practice. We asked four experts during the meeting for their thoughts on what comes next:
• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.
• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.
• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.
• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.
Question: Should ipilimumab and vemurafenib be used together?
Everyone we asked said no, not outside of a clinical trial at least for now. No one knows whether the combination is safe or effective.
Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.
Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.
I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before oncologists begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.
Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren’t what you expect. Don’t just take a patient and give them both and see what happens. That’s not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.
Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.
Question: So which agent would you use first in a patient who has a BRAF mutation?
Again, there was unanimity – with respect to the patient who is very, very sick.
Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.
Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.
The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can’t have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies - the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn’t work, I think vemurafenib.
Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. ... All BRAF-negative patients would see ipilimumab in first line. That is for sure.
Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?
Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don’t have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.
There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.
Question: Will interleukin-2 still have a role in melanoma treatment?
Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. ... We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don’t know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.
Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down... If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it’s not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.
Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients ... and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.
Question: And interferon – Where will it fit in?
Dr. Sondak: We don’t know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn’t sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.
It’s very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.
In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn’t very sturdy to walk on, but we’re trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It’s real exciting – not just the data we already have but for the future and how many patients this will affect positively.
Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.
Euphoria – there is no better word to describe the mood in the melanoma sessions at ASCO. For the first time ever, oncologists have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into community practice. We asked four experts during the meeting for their thoughts on what comes next:
• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.
• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.
• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.
• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.
Question: Should ipilimumab and vemurafenib be used together?
Everyone we asked said no, not outside of a clinical trial at least for now. No one knows whether the combination is safe or effective.
Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.
Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.
I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before oncologists begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.
Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren’t what you expect. Don’t just take a patient and give them both and see what happens. That’s not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.
Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.
Question: So which agent would you use first in a patient who has a BRAF mutation?
Again, there was unanimity – with respect to the patient who is very, very sick.
Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.
Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.
The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can’t have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies - the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn’t work, I think vemurafenib.
Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. ... All BRAF-negative patients would see ipilimumab in first line. That is for sure.
Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?
Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don’t have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.
There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.
Question: Will interleukin-2 still have a role in melanoma treatment?
Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. ... We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don’t know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.
Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down... If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it’s not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.
Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients ... and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.
Question: And interferon – Where will it fit in?
Dr. Sondak: We don’t know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn’t sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.
It’s very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.
In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn’t very sturdy to walk on, but we’re trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It’s real exciting – not just the data we already have but for the future and how many patients this will affect positively.
Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.
Euphoria – there is no better word to describe the mood in the melanoma sessions at ASCO. For the first time ever, oncologists have two new drugs that can prolong the lives of patients with advanced melanoma. They also have a host of questions as to how to bring ipilimumab and vemurafenib into community practice. We asked four experts during the meeting for their thoughts on what comes next:
• Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York; lead author of the BRIM-3 study of vemurafenib vs. dacarbazine in newly diagnosed patients.
• Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center; lead author of the phase III trial showing the efficacy of ipilimumab plus dacarbazine vs. placebo plus dacarbazine in newly diagnosed patients.
• Dr. Vernon K. Sondak, chair of cutaneous oncology and director of surgical education, H. Lee Moffitt Cancer Center & Research Institute in Tampa.
• Dr. Alexander M.M. Eggermont, general director of the Institut de Cancérologie Gustave Roussy in Villejuif, France.
Question: Should ipilimumab and vemurafenib be used together?
Everyone we asked said no, not outside of a clinical trial at least for now. No one knows whether the combination is safe or effective.
Dr. Chapman: We are about to start a phase III trial combining these to see if it is safe and making sure that vemurafenib does not inhibit the effect of ipilimumab. We all hope that this will result in sustained complete responses. That is what we all are looking for.
Dr. Wolchok: The natural next step that many of us are considering is how to integrate these two forms of therapy together. Vemurafenib directly targets the tumor by inhibiting BRAF kinase; ipilimumab really treats the patient by starting an immune reaction that hopefully will control the disease. These are very different approaches to cancer therapy. They are in no way mutually exclusive, and I believe them to be quite complementary.
I think it is important that the combination be explored in a clinical trial because I could make a list of reasons why these two drugs would work together; I could also create a list of reasons why they might not work well together and may even be antagonists. So, I think before oncologists begin to combine potentially approved medications outside of clinical trials, we [need to] have some idea that this is a safe and effective way to go. Until then, I think monotherapy is the best path forward outside of a clinical trial.
Dr. Sondak: If you combine ipilimumab with something else, sometimes the side effects aren’t what you expect. Don’t just take a patient and give them both and see what happens. That’s not safe. You have to do this in a controlled way a research study as quickly as possible because it is the obvious next question.
Dr. Eggermont: I think at this point they should wait at least for the safety data on the combination.
Question: So which agent would you use first in a patient who has a BRAF mutation?
Again, there was unanimity – with respect to the patient who is very, very sick.
Dr. Chapman: I think that is a question is that is still open. Where I am on this question right now is that for a patient who is relatively well, who has a fairly good performance status, I would think about using ipilimumab first because that person may have time to respond to ipilimumab since it does take 3-6 months to have the full effect. On the other hand, a person who has a poor performance status and is sick and does not have time to respond to ipilimumab I would treat that person up-front with vemurafenib.
Dr. Sondak: I think there is going to be uniform agreement throughout the melanoma community that if you have a BRAF-mutant patient with widespread disease, symptomatic disease, high tumor burden that person is going to go immediately on to vemurafenib because nothing else is going to get a rapid response, a rapid resolution of symptoms.
The question is going to be [what to do] for 80% of patients who are BRAF mutant but have much less acute symptomatic disease. Maybe they have some lung metastases, some subcutaneous nodules, [and] they can’t have it all removed surgically but they are still not in dire straits. And I think at our institution we are going to be very motivated to continue to use the immunologic therapies - the IL-2 for some patients, and ipilimumab for many patients because of the possibility that they will get a big benefit at the other end, not an immediate benefit but a long-term benefit. And then if that doesn’t work, I think vemurafenib.
Dr. Eggermont: BRAF-positive patients especially the ones that have rapidly progressive disease or bulky disease that have little time – they will all be treated up front with the BRAF inhibitor. The BRAF-positive patients that have very small disease that is not rapidly progressing could actually also be managed by ipilimumab on first line and only on progression be managed by the BRAF inhibitor because ipilimumab needs more time to work with patients, to kick into activity and into an antitumor effect. ... All BRAF-negative patients would see ipilimumab in first line. That is for sure.
Question: The ipilimumab trial paired ipilimumab with dacarbazine. Is DTIC still an option?
Dr. Wolchok: Looking at the result as someone who has been taking care of patients with melanoma using ipilimumab for several years, I think it is still unknown whether dacarbazine should be added. My own opinion would be to oncologists in the community that if they are going to give ipilimumab at 3 mg/kg to stick with the monotherapy label because we really don’t have data comparing ipilimumab with dacarbazine alone at that dose. And so I think we stick with what we know produces an overall survival benefit.
There are reasons to imagine the addition of dacarbazine could make results better by killing some cancer cells and releasing some antigenic debris that would serve as a target for the immune system. Chemotherapy can also be thought of as changing the tumor microenvironment, which might be advantageous, but chemotherapy could also be immunosuppressive. So we could really make a case either way that dacarbazine added to or detracted from or left things just the same.
Question: Will interleukin-2 still have a role in melanoma treatment?
Dr. Sondak: I am still going to use IL-2, and it makes the most sense if you have someone who uses IL-2 most of time, you will want to use that first before you use anything else. Why? Ipilimumab is tough on the patient. We want them in as good shape as possible. ... We know if they get IL-2 first and then get ipilimumab; the results are just as good, if not better. We don’t know the opposite way. And we also know that a lot of people on ipilimumab get side effects. They wind up on steroids and other immunosuppressive drugs that would make it very difficult to put them on IL-2.
Vemurafenib is going to change a lot of things. A lot of people are too far gone to have surgery, too far gone to have IL-2. Now we have BRAF mutant melanoma [patients] who will get vemurafenib, and shrink down... If we could keep a close eye and figure out when is right time, we are going to do more surgery and maybe IL-2 in those patients because we are going to restore them to place where IL-2 is going to have more room to work. But it’s not going to be 80% of people getting IL-2. It is going to be a very restricted group of people treated by a very specialized group of doctors.
Dr. Eggermont: I think IL-2 will move down in the options list. IL-2 will remain as an option in second or third line, and IL-2 will also be an option in combination with ipilimumab because [Dr.] Steve Rosenberg already did a trial in 36 patients ... and the majority of the complete responders are alive 6 years and longer and are still in complete remission (ASCO 2010, Abstract 8544). The combination of IL-2 and ipilimumab will be relaunched, I am sure.
Question: And interferon – Where will it fit in?
Dr. Sondak: We don’t know how long we should treat people, how intensively, and how we should combine the new and the old, and the data that we have just doesn’t sort it out. On the other hand, if you look at the whole landscape, it actually makes adjuvant treatment with interferon more important now than it used to be.
It’s very clear that interferon treatment does delay recurrences in a substantial fraction of patients. It may not cure many people, but it delays recurrence in quite a few people, and right now today we are so much better off than we were in melanoma 2 years ago and I have no doubt that 2 years from now just with stuff we heard about at this meeting we will be much more clear on how do we use how do we take care of side effects not to mention other new exciting drugs that we hope 2 years from now will start to be available.
In the past we debated, does it even matter that we delay recurrence. The ASCO answer should be, "It absolutely matters to our patients." So interferon and any form of adjuvant therapy is suddenly a bridge. It is a shaky bridge – made with some ropes and a few planks – it isn’t very sturdy to walk on, but we’re trying to get from here, one place where it was safe to another place where hopefully we are better off and not at the bottom of ravine. It’s real exciting – not just the data we already have but for the future and how many patients this will affect positively.
Dr. Eggermont: I think you need to separate the new drugs from the question, what are we going to do in adjuvant? In adjuvant right now, we will still have to wait for about 2.5-3 years for the outcome of the EORTC trial that randomized in double-blind ipilimumab vs. observation in patients with high-risk lymph node positive disease. That answer about ipilimumab in the adjuvant situation will not be there before 2.5 years from now. That means that until then there is only one kid on the block in the adjuvant setting, which is regular interferon, and the currently novel approach of pegylated interferon.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
BRAF Inhibitor Cuts Death Risk in Advanced Melanoma
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.
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (N. Engl. J. Med. 2011 June 5; doi:10.1056NEJMe11057792).
ipilimumab, Yervoy, BRIM-3, ASCO
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (N. Engl. J. Med. 2011 June 5; doi:10.1056NEJMe11057792).
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (N. Engl. J. Med. 2011 June 5; doi:10.1056NEJMe11057792).
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.
ipilimumab, Yervoy, BRIM-3, ASCO
ipilimumab, Yervoy, BRIM-3, ASCO
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: Survival estimates at a median 3 months’ of follow-up suggest 84% of patients treated with vemurafenib would be alive at 6 months vs. 64% of those in a control group treated with dacarbazine.
Data Source: The randomized, open-label, phase III BRIM-3 trial in 675 patients with newly diagnosed stage III or IV melanoma.
Disclosures: 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.
ASCO: BRAF Inhibitor Cuts Death Risk in Advanced Melanoma
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.
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (10.1956NEJMe11057792).
ipilimumab, Yervoy, BRIM-3, ASCO
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (10.1956NEJMe11057792).
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (10.1956NEJMe11057792).
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.
ipilimumab, Yervoy, BRIM-3, ASCO
ipilimumab, Yervoy, BRIM-3, ASCO
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: Survival estimates at a median 3 months' of follow-up suggest 84% of patients treated with vemurafenib would be alive at 6 months vs. 64% of those in a control group treated with dacarbazine.
Data Source: The randomized, open-label, phase III BRIM-3 trial in 675 patients with newly diagnosed stage III or IV melanoma.
Disclosures: 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.
BRAF Inhibitor Cuts Death Risk in Advanced Melanoma
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.
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (10.1956NEJMe11057792).
ipilimumab, Yervoy, BRIM-3, ASCO
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (10.1956NEJMe11057792).
"For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important impact on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment."
Dr. Marc S. Ernstoff of the Dartmouth–Hitchcock Medical Center, Lebanon, N.H., made these comments in an accompanying editorial and reported no relevant financial conflicts (10.1956NEJMe11057792).
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.
ipilimumab, Yervoy, BRIM-3, ASCO
ipilimumab, Yervoy, BRIM-3, ASCO
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: Survival estimates at a median 3 months’ of follow-up suggest 84% of patients treated with vemurafenib would be alive at 6 months vs. 64% of those in a control group treated with dacarbazine.
Data Source: The randomized, open-label, phase III BRIM-3 trial in 675 patients with newly diagnosed stage III or IV melanoma.
Disclosures: 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.
Exemestane Prevents Breast Cancers in Postmenopausal Women
CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.
Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.
Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.
Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.
"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.
Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.
Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.
The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:
• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).
• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).
Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.
Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.
Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.
Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.
Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.
"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.
The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.
Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.
Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.
Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.
Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.
"[Patients] and practitioners now have three options for breast cancer chemoprevention: tamoxifen, raloxifene, and exemestane – agents of proven efficacy that are among the best-studied drugs in the world. Breast cancer is the second most common cause of death from cancer and one of the most feared diagnoses for women in the United States. We have the knowledge and tools to reduce its incidence today. We have run out of excuses. What are we waiting for?"
Dr. Nancy E. Davidson and Thomas W. Kensler, Ph.D., are from the University of Pittsburgh Cancer Institute and UPMC Cancer Centers in Pittsburg. Their comments appeared in an editorial accompanying the study in the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJM1106052).The editorialists disclosed no relevant conflicts of interest.
"[Patients] and practitioners now have three options for breast cancer chemoprevention: tamoxifen, raloxifene, and exemestane – agents of proven efficacy that are among the best-studied drugs in the world. Breast cancer is the second most common cause of death from cancer and one of the most feared diagnoses for women in the United States. We have the knowledge and tools to reduce its incidence today. We have run out of excuses. What are we waiting for?"
Dr. Nancy E. Davidson and Thomas W. Kensler, Ph.D., are from the University of Pittsburgh Cancer Institute and UPMC Cancer Centers in Pittsburg. Their comments appeared in an editorial accompanying the study in the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJM1106052).The editorialists disclosed no relevant conflicts of interest.
"[Patients] and practitioners now have three options for breast cancer chemoprevention: tamoxifen, raloxifene, and exemestane – agents of proven efficacy that are among the best-studied drugs in the world. Breast cancer is the second most common cause of death from cancer and one of the most feared diagnoses for women in the United States. We have the knowledge and tools to reduce its incidence today. We have run out of excuses. What are we waiting for?"
Dr. Nancy E. Davidson and Thomas W. Kensler, Ph.D., are from the University of Pittsburgh Cancer Institute and UPMC Cancer Centers in Pittsburg. Their comments appeared in an editorial accompanying the study in the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJM1106052).The editorialists disclosed no relevant conflicts of interest.
CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.
Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.
Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.
Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.
"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.
Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.
Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.
The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:
• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).
• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).
Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.
Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.
Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.
Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.
Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.
"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.
The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.
Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.
Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.
Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.
Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.
CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.
Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.
Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.
Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.
"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.
Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.
Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.
The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:
• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).
• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).
Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.
Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.
Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.
Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.
Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.
"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.
The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.
Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.
Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.
Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.
Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: The annual incidence of invasive breast cancer was 0.19% with exemestane vs. 0.55% with placebo (hazard ratio 0.35, P = .002).
Data Source: A randomized, double-blind, placebo-controlled chemoprevention trial in 4,560 postmenopausal women at risk of breast cancer.
Disclosures: Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.