› Forums › General Melanoma Community › Inaccurate Zelboraf approval wording?
- This topic has 22 replies, 7 voices, and was last updated 12 years, 8 months ago by
scotito.
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- August 17, 2011 at 10:55 pm
Has anyone seen exactly what " Zelboraf" was FDA approved for. The write ups on the approval that i have seen refers to THE BRAF mutation.
As many of us know there are many BRAF mutations and Essentially all of the (Plexxikon, Roche/Genentech) PLX-4032 trials were limited to one BRAF DNA mutation (V600E).
One question is what will insurance companies cover if one has another of the BRAF mutations and wants to try the Zelborat off-label for their BRAF mutation?
People also need to be aware that Roche/Genentech's BRAF test states that one is BRAF negative if one has a different BRAF mutation than the V600E. They should state that one is V600E negative or should test for all know BRAF DNA mutations.
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- August 17, 2011 at 11:35 pm
As is often the case, there is confusion surrounding FDA approval of something, but here is the actual statement from the FDA http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm.
Just as there was some months ago when Ipilimumab was approved, there will be a flurry of questions about insurance approval, cost, availability and , prescribing indications.
Because I always cast a jaundiced eye upon melanoma treatments and/or clinical trials of any kind to sort through the chafe of hype and realities, I do have some questions as well.
Although I welcome this new approval, it is important that we all look beyond the hype of "game changer" and recognize that BRAF has shown to be temporary at best for reducing tumor burden and of itself has not been to show durability. That it can reduce tumor burden in the short term and open a window for other treatments in the long term is important.
I have yet to see, despite numerous inquiries, that the BRAF mutation exists in 50% of all melanomas. Perhaps 50% of those TESTED, but how many in the melanoma population have been tested? I just do not believe that 50% of all of us have the BRAF mutation sans medical proof.
I know this is far beyond the scope of your post, but I am quite concerned that by shutting down this particular pathway, there is a high risk of lighting an inferno of melanoma once it finds a workaround to this particular pathway.
More than one patient here has been a participant in an inhibitor trial, had fantastic vanishing of tumors , sometimes within days,only to find some months or weeks later that melanoma was everywhere and killed them as a result…..often within days as well.
But, I digress. Check the above link of what BRAF and the test were approved for.
Cheers,
Charlie S
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- August 17, 2011 at 11:53 pm
Actually, Charlie, you did a beautiful job of amplifying the aim of my original post. The one thing you said that I didn't totally agree with was "THE BRAF" mutatioin!
The URL you posted covered my expectation of the limitation on the approval. Thank you for that URL, I knew it should be available somewhere. As you also noted, follow on is needed, so it will be good to see what BRAF mutation meds and MEK and other new drugs to intersect the signaling pathways at other point will make. Hopefuly will have at least an additive effect.
Have you seen what the testing restrictions are going to be on the successor to Zeboraf that the same company is working on?
Will be interesting to see what the other company that is testing on other BRAF mutations comes up with as well.
Yes, this is a nice start, BUT still a long ways from the end. ANOTHER step.
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- August 17, 2011 at 11:53 pm
Actually, Charlie, you did a beautiful job of amplifying the aim of my original post. The one thing you said that I didn't totally agree with was "THE BRAF" mutatioin!
The URL you posted covered my expectation of the limitation on the approval. Thank you for that URL, I knew it should be available somewhere. As you also noted, follow on is needed, so it will be good to see what BRAF mutation meds and MEK and other new drugs to intersect the signaling pathways at other point will make. Hopefuly will have at least an additive effect.
Have you seen what the testing restrictions are going to be on the successor to Zeboraf that the same company is working on?
Will be interesting to see what the other company that is testing on other BRAF mutations comes up with as well.
Yes, this is a nice start, BUT still a long ways from the end. ANOTHER step.
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- August 18, 2011 at 2:04 am
I'm with you, Charlie and Jerry. We've spent some time looking at this professionally (and me personally), and I'm not particularly confident of the 50% number either. Originally, the number was put at 60%, with 85% of those with mutated B-RAF having the V600 mutation. Over time, the public number has slid lower, and mention of the idea that there are more B-RAF mutations than simply the V600 has virtually disappeared.
As I write this, I realize that one place to look for some numbers might be the approval for the cobas 4800 test, which should have been conducted with a ranbdom population of melanoma patients. Has anyone seen those numbers? I'm going looking for them now…
In the meantime and to be lazy, has anyone seen a broad population test on this issue?
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- August 18, 2011 at 2:04 am
I'm with you, Charlie and Jerry. We've spent some time looking at this professionally (and me personally), and I'm not particularly confident of the 50% number either. Originally, the number was put at 60%, with 85% of those with mutated B-RAF having the V600 mutation. Over time, the public number has slid lower, and mention of the idea that there are more B-RAF mutations than simply the V600 has virtually disappeared.
As I write this, I realize that one place to look for some numbers might be the approval for the cobas 4800 test, which should have been conducted with a ranbdom population of melanoma patients. Has anyone seen those numbers? I'm going looking for them now…
In the meantime and to be lazy, has anyone seen a broad population test on this issue?
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- August 26, 2011 at 7:20 am
Charlie – thank you for that post. i am actually as of yesterday one of those game changer people. very heady and exciting reaction from all those around me. but no one would even address or acknowledge your point about the efficacy after a month or two. and recurrence. it was like a taboo subject matter. while i or anyone cant get around the joy of extra time – i am amazed how quickly all involved skipped over this. the actual reality still "in play". so yes – i would agree one continues to look at it optimistically but realistically.
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- August 26, 2011 at 7:20 am
Charlie – thank you for that post. i am actually as of yesterday one of those game changer people. very heady and exciting reaction from all those around me. but no one would even address or acknowledge your point about the efficacy after a month or two. and recurrence. it was like a taboo subject matter. while i or anyone cant get around the joy of extra time – i am amazed how quickly all involved skipped over this. the actual reality still "in play". so yes – i would agree one continues to look at it optimistically but realistically.
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- August 17, 2011 at 11:35 pm
As is often the case, there is confusion surrounding FDA approval of something, but here is the actual statement from the FDA http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm.
Just as there was some months ago when Ipilimumab was approved, there will be a flurry of questions about insurance approval, cost, availability and , prescribing indications.
Because I always cast a jaundiced eye upon melanoma treatments and/or clinical trials of any kind to sort through the chafe of hype and realities, I do have some questions as well.
Although I welcome this new approval, it is important that we all look beyond the hype of "game changer" and recognize that BRAF has shown to be temporary at best for reducing tumor burden and of itself has not been to show durability. That it can reduce tumor burden in the short term and open a window for other treatments in the long term is important.
I have yet to see, despite numerous inquiries, that the BRAF mutation exists in 50% of all melanomas. Perhaps 50% of those TESTED, but how many in the melanoma population have been tested? I just do not believe that 50% of all of us have the BRAF mutation sans medical proof.
I know this is far beyond the scope of your post, but I am quite concerned that by shutting down this particular pathway, there is a high risk of lighting an inferno of melanoma once it finds a workaround to this particular pathway.
More than one patient here has been a participant in an inhibitor trial, had fantastic vanishing of tumors , sometimes within days,only to find some months or weeks later that melanoma was everywhere and killed them as a result…..often within days as well.
But, I digress. Check the above link of what BRAF and the test were approved for.
Cheers,
Charlie S
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- August 18, 2011 at 9:01 pm
This is a great conversation, and really digs into some interesting issues. Early studies suggested a very high rate of BRAF mutation for cutaneous melanoma, but as more data became available the numbers have dropped. I have not seen a metaanalysis of all the smaller studies for mutation rates, but am still looking. In the meantime, here is a literature review that summarizes the studies that have been done in this area: http://omim.org/entry/164757
The BRIM 2 study that was part of the FDA's decision analyzed 328 patients using the "cobas" test for V600E mutation. Of that group 56% tested positive.
The approval of Zelboraf specifies that patients must test positive using an FDA approved test. Currently the only approved test is the "cobas" test that is made by Roche, the parent company that makes Zelboraf. Other companies make BRAF test kits, but they have not filed for nor received FDA approval. It will be interesting to see if that changes now that the approval has taken place.
cobas is supposedly specific for the V600E mutation, and the numbers I have seen suggest that of BRAF mutations in melanoma patients 88% were V600E, 5.4% were V600K, and the rest are spread fairly thinly among many other mutations in the BRAF sequence. It is possible that some people with non-E mutations will respond to Zelboraf, but that would have to be done under a clinical trial I believe. I strongly doubt that insurance would cover the drug for someone who did not test positive for the V600E mutation.
If I get more information on the meta-analysis of the mutation stats I will post separately.
Tim–MRF
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- August 18, 2011 at 9:01 pm
This is a great conversation, and really digs into some interesting issues. Early studies suggested a very high rate of BRAF mutation for cutaneous melanoma, but as more data became available the numbers have dropped. I have not seen a metaanalysis of all the smaller studies for mutation rates, but am still looking. In the meantime, here is a literature review that summarizes the studies that have been done in this area: http://omim.org/entry/164757
The BRIM 2 study that was part of the FDA's decision analyzed 328 patients using the "cobas" test for V600E mutation. Of that group 56% tested positive.
The approval of Zelboraf specifies that patients must test positive using an FDA approved test. Currently the only approved test is the "cobas" test that is made by Roche, the parent company that makes Zelboraf. Other companies make BRAF test kits, but they have not filed for nor received FDA approval. It will be interesting to see if that changes now that the approval has taken place.
cobas is supposedly specific for the V600E mutation, and the numbers I have seen suggest that of BRAF mutations in melanoma patients 88% were V600E, 5.4% were V600K, and the rest are spread fairly thinly among many other mutations in the BRAF sequence. It is possible that some people with non-E mutations will respond to Zelboraf, but that would have to be done under a clinical trial I believe. I strongly doubt that insurance would cover the drug for someone who did not test positive for the V600E mutation.
If I get more information on the meta-analysis of the mutation stats I will post separately.
Tim–MRF
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- August 18, 2011 at 10:44 pm
guys, keep digging for info…very helpful for those of us V600E…..i just found out that i was passed on braf/mek trial but now will be given zelboraf and i haven't had time to research this…i am out of control and hope this is a stepping stone for me to stay topside…
boots
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- August 19, 2011 at 2:45 am
Dammit Boots, do either of us ever get a break? Don's moving to a new treatment as well…hopefully this one…
Michelle, wife of Don
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- August 19, 2011 at 2:45 am
Dammit Boots, do either of us ever get a break? Don's moving to a new treatment as well…hopefully this one…
Michelle, wife of Don
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- August 18, 2011 at 10:44 pm
guys, keep digging for info…very helpful for those of us V600E…..i just found out that i was passed on braf/mek trial but now will be given zelboraf and i haven't had time to research this…i am out of control and hope this is a stepping stone for me to stay topside…
boots
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- August 19, 2011 at 12:59 am
Thanks for the highly informative link Tim; while I dig in and absorb that, I'm wondering if because "cobas" is proprietary to V600E , the other testing companies may not be V600E specific and are more expansive while looking at other sub set pathways as well such as Mark pathway reactivation, Kinase COT overexpression, CRAF activation, NRAS or MEK1 mutation for their own research?
Because there is a host of studies about pathways, that would certainly explain them not applying for FDA testing approval at this time.
In the meantime, thanks again for the link;; because so many patients get wrapped up in numbers, it is important to know their basis.
Cheers,
Charlie S
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- August 19, 2011 at 1:33 pm
My impression in speaking with researchers is that the other tests are just as good, just as specific. The key is to be sure the test is done at a CLIA certified lab (Clinical Laboratory Improvement Amendments). Roche has a large diagnostic component, so it makes sense for them to co-develop the "cobas" test with the BRAF drug. My understanding is that the GSK BRAF inhibitor, which also targets V600E, only requires a positive test, but doesn't specify which test.
The idea of activation of other pathways is, I think, important. If doctors could test for activation of alternate pathways before giving BRAF inhibitors it might predict who would respond. Then they would only give the drugs to people who will benefit.
Tim–MRF
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- August 19, 2011 at 1:33 pm
My impression in speaking with researchers is that the other tests are just as good, just as specific. The key is to be sure the test is done at a CLIA certified lab (Clinical Laboratory Improvement Amendments). Roche has a large diagnostic component, so it makes sense for them to co-develop the "cobas" test with the BRAF drug. My understanding is that the GSK BRAF inhibitor, which also targets V600E, only requires a positive test, but doesn't specify which test.
The idea of activation of other pathways is, I think, important. If doctors could test for activation of alternate pathways before giving BRAF inhibitors it might predict who would respond. Then they would only give the drugs to people who will benefit.
Tim–MRF
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- August 19, 2011 at 12:59 am
Thanks for the highly informative link Tim; while I dig in and absorb that, I'm wondering if because "cobas" is proprietary to V600E , the other testing companies may not be V600E specific and are more expansive while looking at other sub set pathways as well such as Mark pathway reactivation, Kinase COT overexpression, CRAF activation, NRAS or MEK1 mutation for their own research?
Because there is a host of studies about pathways, that would certainly explain them not applying for FDA testing approval at this time.
In the meantime, thanks again for the link;; because so many patients get wrapped up in numbers, it is important to know their basis.
Cheers,
Charlie S
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- August 19, 2011 at 4:58 am
Tim, Thanks again. I will look at the link you posted. Am loading the car now to leave Friday to go to Colorada for the birth of my 15th living grand child and 1st great grandchild. I would like to see numbers that relate to the locations that may also contin c-kit. Ii munderstand that c-kit and BRAF are mutjally exclusive. I have seen many people with mucaousal melanoma though that were not c-kit positive. Would suspect thjat an across the board run with mucousal melanoma included would likely lower the % that includes BRAF V600E.
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- August 19, 2011 at 1:39 pm
Jerry:
Congratulations on the expanded family! I have to say that every time I see you post I think about how close we came to losing you. Greatful that even though the horse won the battle, you won the war.
C-kit numbers are pretty low except in mucosal and acral melanoma. I have seen the numbers, but have not looked into the studies behind those numbers. I can try to find out.
I have heard that BRAF and NRAS mutations are mutually exclusive, so am not surprised to hear this about c-kit. When I have pushed on this the explanations I get are not very satisfactory. Basically I was told that the odds of a normal cell developing any mutation are high, and so the odds of a single cell developing two big mutations are astronomical. In other words, the idea that they are mutually exclusive is based on probability rather than science. Again, I would like to know more about this and understand it better. We certainly know that a mutated cell line, resulting in a tumor, can over time develop other mutations.
Safe travels. I am sure you will enjoy the cooler weather in Colorado.
Tim—MRF
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- August 19, 2011 at 1:39 pm
Jerry:
Congratulations on the expanded family! I have to say that every time I see you post I think about how close we came to losing you. Greatful that even though the horse won the battle, you won the war.
C-kit numbers are pretty low except in mucosal and acral melanoma. I have seen the numbers, but have not looked into the studies behind those numbers. I can try to find out.
I have heard that BRAF and NRAS mutations are mutually exclusive, so am not surprised to hear this about c-kit. When I have pushed on this the explanations I get are not very satisfactory. Basically I was told that the odds of a normal cell developing any mutation are high, and so the odds of a single cell developing two big mutations are astronomical. In other words, the idea that they are mutually exclusive is based on probability rather than science. Again, I would like to know more about this and understand it better. We certainly know that a mutated cell line, resulting in a tumor, can over time develop other mutations.
Safe travels. I am sure you will enjoy the cooler weather in Colorado.
Tim—MRF
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- August 19, 2011 at 4:58 am
Tim, Thanks again. I will look at the link you posted. Am loading the car now to leave Friday to go to Colorada for the birth of my 15th living grand child and 1st great grandchild. I would like to see numbers that relate to the locations that may also contin c-kit. Ii munderstand that c-kit and BRAF are mutjally exclusive. I have seen many people with mucaousal melanoma though that were not c-kit positive. Would suspect thjat an across the board run with mucousal melanoma included would likely lower the % that includes BRAF V600E.
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