Benefits of BRAF Inhibitor Confirmed in Metastatic Melanoma

Phase II trial data confirm that an experimental BRAF inhibitor dramatically shrinks tumors and extends time to disease progression in patients with previously treated BRAF V600 mutation–positive metastatic melanoma, according to a report presented Nov. 5 at the seventh international congress of the Society for Melanoma Research in Sydney.

Of the 132 patients in the BRIM2 trial who received RG7204, also known as PLX4032, 52% responded with tumor shrinkage of at least 30% for at least two consecutive CT scans as assessed by independent review.

In all, 82% of patients had either a response (complete response in 3 patients, partial response in 66) or stable disease (39 patients). The median duration of response was 6.8 months.

Median progression-free survival reached 6.2 months, Dr. Jeffrey Sosman said at the meeting. After a median follow-up of approximately 7 months, 38% of patients were still on treatment.

"I think the response duration being just over 6 months is a very, very significant advance," co-investigator Dr. Rene Gonzalez said in an interview. "The normal time to progression in one of these patients is 6 to 8 weeks, so this is almost a tripling of their progression-free survival."

Both investigators pointed out that the findings confirm earlier data (N. Engl. J. Med. 2010;363:809-19), in which 81% of patients with the BRAF mutation treated with RG7204 had at least 30% tumor shrinkage. No significant predictors of progression or response were identified, except for original tumor size and number.

Dr. Gonzalez said he has no doubt RG7204 will be approved; the question is whether the Food and Drug Administration will do so based on the phase II data or wait until completion of the ongoing phase III BRIM3 trial evaluating overall survival with RG7204 vs. the standard of care, dacarbazine, in patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. The primary end point in that trial is overall survival.

The anti-CTLA4 antibody ipilimumab is also poised for approval after becoming the first drug to show a survival advantage in refractory melanoma in a phase III trial, but it has problems, particularly with toxicity, said Dr. Gonzalez, who worked on trials for both drugs. "I think for a community practitioner, this drug [RG7204], I have no doubt would be the first-line choice, if they had an option," he said.

In the current trial patients received RG7204 at a dose of 960 mg twice daily. Grade 3 or greater adverse events were abnormal liver function (14%), joint pain/arthritis (11%) and dysphagia/pancreatitis (10%). The most common adverse events were rash, photosensitivity, hair loss, and joint pain, reported Dr. Sosman, director of the melanoma and tumor immunotherapy program, Vanderbilt-Ingram Cancer Center, Nashville, Tenn. The secondary end point of overall survival had not yet been reached.

RG7204, which is being codeveloped by Roche Pharmaceuticals and Plexxikon, is a small molecule designed to selectively inhibit the mutated form of the BRAF protein. It is estimated that BRAF mutations are present in about half of melanomas, of which 90% are BRAF V600 mutations.

RG7204 may benefit patients with other BRAF mutations, but there are much less data in this small population, said Dr. Gonzalez, professor of medicine and director of the University of Colorado at Denver Melanoma Research Clinic.

So far, the Achilles’ heel of RG7204 appears to be resistance. "If you have a patient with a duration of 6 months, you do get resistance," Dr. Gonzalez said. Strides have been made to understand the mechanism of resistance, but one logical solution would be to combine RG7204 with an anti-CTLA4-antibody, which tends not to work as fast but has responses that seem to be more durable, he said, adding, "That buys us some time."

It might also be possible to abrogate resistance by blocking both the RAF and MEK pathways or by using pan-RAF inhibitors like RAF265 (Novartis Oncology) that block not only BRAF, but other RAF genes, he said.

Pending a decision by the FDA, plans are underway to open an expanded access program to make RG7204 available to patients with BRAF-mutation–positive advanced melanoma who have received at least one prior treatment, according to Dr. Hal Barron, head of Genentech’s global product development and chief medical officer.

"People with advanced melanoma urgently need more options for treatment and we will continue to work with global health authorities to gather the necessary data to bring this medicine to people with this type of cancer," Dr. Barron said in a statement.

BRIM2 was sponsored by Genentech and Hoffman-La Roche Ltd. Dr. Sosman has received grant support from Roche and Plexxikon.

Phase II trial data confirm that an experimental BRAF inhibitor dramatically shrinks tumors and extends time to disease progression in patients with previously treated BRAF V600 mutation–positive metastatic melanoma, according to a report presented Nov. 5 at the seventh international congress of the Society for Melanoma Research in Sydney.

Of the 132 patients in the BRIM2 trial who received RG7204, also known as PLX4032, 52% responded with tumor shrinkage of at least 30% for at least two consecutive CT scans as assessed by independent review.

In all, 82% of patients had either a response (complete response in 3 patients, partial response in 66) or stable disease (39 patients). The median duration of response was 6.8 months.

Median progression-free survival reached 6.2 months, Dr. Jeffrey Sosman said at the meeting. After a median follow-up of approximately 7 months, 38% of patients were still on treatment.

"I think the response duration being just over 6 months is a very, very significant advance," co-investigator Dr. Rene Gonzalez said in an interview. "The normal time to progression in one of these patients is 6 to 8 weeks, so this is almost a tripling of their progression-free survival."

Both investigators pointed out that the findings confirm earlier data (N. Engl. J. Med. 2010;363:809-19), in which 81% of patients with the BRAF mutation treated with RG7204 had at least 30% tumor shrinkage. No significant predictors of progression or response were identified, except for original tumor size and number.

Dr. Gonzalez said he has no doubt RG7204 will be approved; the question is whether the Food and Drug Administration will do so based on the phase II data or wait until completion of the ongoing phase III BRIM3 trial evaluating overall survival with RG7204 vs. the standard of care, dacarbazine, in patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. The primary end point in that trial is overall survival.

The anti-CTLA4 antibody ipilimumab is also poised for approval after becoming the first drug to show a survival advantage in refractory melanoma in a phase III trial, but it has problems, particularly with toxicity, said Dr. Gonzalez, who worked on trials for both drugs. "I think for a community practitioner, this drug [RG7204], I have no doubt would be the first-line choice, if they had an option," he said.

In the current trial patients received RG7204 at a dose of 960 mg twice daily. Grade 3 or greater adverse events were abnormal liver function (14%), joint pain/arthritis (11%) and dysphagia/pancreatitis (10%). The most common adverse events were rash, photosensitivity, hair loss, and joint pain, reported Dr. Sosman, director of the melanoma and tumor immunotherapy program, Vanderbilt-Ingram Cancer Center, Nashville, Tenn. The secondary end point of overall survival had not yet been reached.

RG7204, which is being codeveloped by Roche Pharmaceuticals and Plexxikon, is a small molecule designed to selectively inhibit the mutated form of the BRAF protein. It is estimated that BRAF mutations are present in about half of melanomas, of which 90% are BRAF V600 mutations.

RG7204 may benefit patients with other BRAF mutations, but there are much less data in this small population, said Dr. Gonzalez, professor of medicine and director of the University of Colorado at Denver Melanoma Research Clinic.

So far, the Achilles’ heel of RG7204 appears to be resistance. "If you have a patient with a duration of 6 months, you do get resistance," Dr. Gonzalez said. Strides have been made to understand the mechanism of resistance, but one logical solution would be to combine RG7204 with an anti-CTLA4-antibody, which tends not to work as fast but has responses that seem to be more durable, he said, adding, "That buys us some time."

It might also be possible to abrogate resistance by blocking both the RAF and MEK pathways or by using pan-RAF inhibitors like RAF265 (Novartis Oncology) that block not only BRAF, but other RAF genes, he said.

Pending a decision by the FDA, plans are underway to open an expanded access program to make RG7204 available to patients with BRAF-mutation–positive advanced melanoma who have received at least one prior treatment, according to Dr. Hal Barron, head of Genentech’s global product development and chief medical officer.

"People with advanced melanoma urgently need more options for treatment and we will continue to work with global health authorities to gather the necessary data to bring this medicine to people with this type of cancer," Dr. Barron said in a statement.

BRIM2 was sponsored by Genentech and Hoffman-La Roche Ltd. Dr. Sosman has received grant support from Roche and Plexxikon.

Phase II trial data confirm that an experimental BRAF inhibitor dramatically shrinks tumors and extends time to disease progression in patients with previously treated BRAF V600 mutation–positive metastatic melanoma, according to a report presented Nov. 5 at the seventh international congress of the Society for Melanoma Research in Sydney.

Of the 132 patients in the BRIM2 trial who received RG7204, also known as PLX4032, 52% responded with tumor shrinkage of at least 30% for at least two consecutive CT scans as assessed by independent review.

In all, 82% of patients had either a response (complete response in 3 patients, partial response in 66) or stable disease (39 patients). The median duration of response was 6.8 months.

Median progression-free survival reached 6.2 months, Dr. Jeffrey Sosman said at the meeting. After a median follow-up of approximately 7 months, 38% of patients were still on treatment.

"I think the response duration being just over 6 months is a very, very significant advance," co-investigator Dr. Rene Gonzalez said in an interview. "The normal time to progression in one of these patients is 6 to 8 weeks, so this is almost a tripling of their progression-free survival."

Both investigators pointed out that the findings confirm earlier data (N. Engl. J. Med. 2010;363:809-19), in which 81% of patients with the BRAF mutation treated with RG7204 had at least 30% tumor shrinkage. No significant predictors of progression or response were identified, except for original tumor size and number.

Dr. Gonzalez said he has no doubt RG7204 will be approved; the question is whether the Food and Drug Administration will do so based on the phase II data or wait until completion of the ongoing phase III BRIM3 trial evaluating overall survival with RG7204 vs. the standard of care, dacarbazine, in patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. The primary end point in that trial is overall survival.

The anti-CTLA4 antibody ipilimumab is also poised for approval after becoming the first drug to show a survival advantage in refractory melanoma in a phase III trial, but it has problems, particularly with toxicity, said Dr. Gonzalez, who worked on trials for both drugs. "I think for a community practitioner, this drug [RG7204], I have no doubt would be the first-line choice, if they had an option," he said.

In the current trial patients received RG7204 at a dose of 960 mg twice daily. Grade 3 or greater adverse events were abnormal liver function (14%), joint pain/arthritis (11%) and dysphagia/pancreatitis (10%). The most common adverse events were rash, photosensitivity, hair loss, and joint pain, reported Dr. Sosman, director of the melanoma and tumor immunotherapy program, Vanderbilt-Ingram Cancer Center, Nashville, Tenn. The secondary end point of overall survival had not yet been reached.

RG7204, which is being codeveloped by Roche Pharmaceuticals and Plexxikon, is a small molecule designed to selectively inhibit the mutated form of the BRAF protein. It is estimated that BRAF mutations are present in about half of melanomas, of which 90% are BRAF V600 mutations.

RG7204 may benefit patients with other BRAF mutations, but there are much less data in this small population, said Dr. Gonzalez, professor of medicine and director of the University of Colorado at Denver Melanoma Research Clinic.

So far, the Achilles’ heel of RG7204 appears to be resistance. "If you have a patient with a duration of 6 months, you do get resistance," Dr. Gonzalez said. Strides have been made to understand the mechanism of resistance, but one logical solution would be to combine RG7204 with an anti-CTLA4-antibody, which tends not to work as fast but has responses that seem to be more durable, he said, adding, "That buys us some time."

It might also be possible to abrogate resistance by blocking both the RAF and MEK pathways or by using pan-RAF inhibitors like RAF265 (Novartis Oncology) that block not only BRAF, but other RAF genes, he said.

Pending a decision by the FDA, plans are underway to open an expanded access program to make RG7204 available to patients with BRAF-mutation–positive advanced melanoma who have received at least one prior treatment, according to Dr. Hal Barron, head of Genentech’s global product development and chief medical officer.

"People with advanced melanoma urgently need more options for treatment and we will continue to work with global health authorities to gather the necessary data to bring this medicine to people with this type of cancer," Dr. Barron said in a statement.

BRIM2 was sponsored by Genentech and Hoffman-La Roche Ltd. Dr. Sosman has received grant support from Roche and Plexxikon.