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.

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.