Well, my first thought was that if your husband had responded well to ipi, perhaps following up with IL-2 might enhance that good response. However, since your husband had a bad experience with ipi– even life threatening– I would be cautious about IL-2 or even anti-PD1. My guess is that is the reason that Dr. Weber recommended sticking with the BRAF drugs. 

Tim Turnham, the executive director of MRF and one of our members, Kylez, recently attended a melanoma medical conference. See this thread: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/some-treatment-option-updates#comment-72466

One of the speakers said that Tafinlar + MEK can work after progressing on Zelboraf. The combo works in BRAF naive patients better than it works in Zelboraf treated patients, but it can work. Hopefully, Kyle will be able to provide you with more information.

Other than that, Mat's suggestions that you contact Catherine Poole at the Melanoma International Foundation about clinical trials or that you consider antibody-drug conjugates (ADCs) are good suggestions. However, you will probably need to get the results of your husband's brain MRI before you can seriously consider clinicial trials; most of them exclude patients with brain mets. You might also look into targeted therapies directed towards other mutations like NRAS and c-KIT. 

Don't give up! Keep fighting! There are so many promising treatments now that you never know which one will be the right one for you. Let us know how the brain MRI comes out and what the lastest opinion is about your husband's possible leptomeningeal disease. 

Well, my first thought was that if your husband had responded well to ipi, perhaps following up with IL-2 might enhance that good response. However, since your husband had a bad experience with ipi– even life threatening– I would be cautious about IL-2 or even anti-PD1. My guess is that is the reason that Dr. Weber recommended sticking with the BRAF drugs. 

Tim Turnham, the executive director of MRF and one of our members, Kylez, recently attended a melanoma medical conference. See this thread: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/some-treatment-option-updates#comment-72466

One of the speakers said that Tafinlar + MEK can work after progressing on Zelboraf. The combo works in BRAF naive patients better than it works in Zelboraf treated patients, but it can work. Hopefully, Kyle will be able to provide you with more information.

Other than that, Mat's suggestions that you contact Catherine Poole at the Melanoma International Foundation about clinical trials or that you consider antibody-drug conjugates (ADCs) are good suggestions. However, you will probably need to get the results of your husband's brain MRI before you can seriously consider clinicial trials; most of them exclude patients with brain mets. You might also look into targeted therapies directed towards other mutations like NRAS and c-KIT. 

Don't give up! Keep fighting! There are so many promising treatments now that you never know which one will be the right one for you. Let us know how the brain MRI comes out and what the lastest opinion is about your husband's possible leptomeningeal disease. 

Well, my first thought was that if your husband had responded well to ipi, perhaps following up with IL-2 might enhance that good response. However, since your husband had a bad experience with ipi– even life threatening– I would be cautious about IL-2 or even anti-PD1. My guess is that is the reason that Dr. Weber recommended sticking with the BRAF drugs. 

Tim Turnham, the executive director of MRF and one of our members, Kylez, recently attended a melanoma medical conference. See this thread: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/some-treatment-option-updates#comment-72466

One of the speakers said that Tafinlar + MEK can work after progressing on Zelboraf. The combo works in BRAF naive patients better than it works in Zelboraf treated patients, but it can work. Hopefully, Kyle will be able to provide you with more information.

Other than that, Mat's suggestions that you contact Catherine Poole at the Melanoma International Foundation about clinical trials or that you consider antibody-drug conjugates (ADCs) are good suggestions. However, you will probably need to get the results of your husband's brain MRI before you can seriously consider clinicial trials; most of them exclude patients with brain mets. You might also look into targeted therapies directed towards other mutations like NRAS and c-KIT. 

Don't give up! Keep fighting! There are so many promising treatments now that you never know which one will be the right one for you. Let us know how the brain MRI comes out and what the lastest opinion is about your husband's possible leptomeningeal disease. 

Joy, my recollection of what Dr. Weber said is, I believe, in line with what your melanoma doc said. It's not what POW is suggesting. My memory of what was said is — that the earlier one starts BRAF (he used term generically) +MEK together the better. Starting them simultaneously being the best. Whereas the more time one is on the single BRAF agent, the less benefit adding MEK will have (on average), as the point is to block 2 pathways simultaneously making the resistance hurdle hard to overcome. 

POW, I had replied to someone on another forum about MEK+BRAF — maybe that is where you got that idea — but I went back later and saw the person in question had already had developed resistance to Z, making my comment about adding MEK+BRAF almost certainly (and unfortunately) irrelevant.

Joy, my recollection of what Dr. Weber said is, I believe, in line with what your melanoma doc said. It's not what POW is suggesting. My memory of what was said is — that the earlier one starts BRAF (he used term generically) +MEK together the better. Starting them simultaneously being the best. Whereas the more time one is on the single BRAF agent, the less benefit adding MEK will have (on average), as the point is to block 2 pathways simultaneously making the resistance hurdle hard to overcome. 

POW, I had replied to someone on another forum about MEK+BRAF — maybe that is where you got that idea — but I went back later and saw the person in question had already had developed resistance to Z, making my comment about adding MEK+BRAF almost certainly (and unfortunately) irrelevant.

Joy, my recollection of what Dr. Weber said is, I believe, in line with what your melanoma doc said. It's not what POW is suggesting. My memory of what was said is — that the earlier one starts BRAF (he used term generically) +MEK together the better. Starting them simultaneously being the best. Whereas the more time one is on the single BRAF agent, the less benefit adding MEK will have (on average), as the point is to block 2 pathways simultaneously making the resistance hurdle hard to overcome. 

POW, I had replied to someone on another forum about MEK+BRAF — maybe that is where you got that idea — but I went back later and saw the person in question had already had developed resistance to Z, making my comment about adding MEK+BRAF almost certainly (and unfortunately) irrelevant.

Kyle, thank you for clarifying some of what you learned at the recent melanoma meeting. What you reported makes sense– it is better to start with a BRAF+Mek combo than with a BRAF inhibitor alone. I think there is compelling evidence to support that.

My question– actually a question a lot of patients here have– is if you have already progressed on a BRAF (usually Zelboraf) monotherapy will it do any good to start on Tafinlar + Mekinist? I can't seem to find any published reports about that. 

In Tim Turnham's report on the same meeting he said, "Data now shows that people who have progressed on BRAF monotherapy do not perform as well on the combination as do people who have not had prior BRAF therapy.  This suggests it is better to start with the combination." [emphasis mine] I interpreted this to mean that people who had prior BRAF monotherapy can benefit from the combination, but not as many of them benefit. Perhaps I misinterpreted what Tim said. Can you shed any additional light on the advisability of trying Tafinlar + Mekinist after progressing on Zelboraf?

Kyle, thank you for clarifying some of what you learned at the recent melanoma meeting. What you reported makes sense– it is better to start with a BRAF+Mek combo than with a BRAF inhibitor alone. I think there is compelling evidence to support that.

My question– actually a question a lot of patients here have– is if you have already progressed on a BRAF (usually Zelboraf) monotherapy will it do any good to start on Tafinlar + Mekinist? I can't seem to find any published reports about that. 

In Tim Turnham's report on the same meeting he said, "Data now shows that people who have progressed on BRAF monotherapy do not perform as well on the combination as do people who have not had prior BRAF therapy.  This suggests it is better to start with the combination." [emphasis mine] I interpreted this to mean that people who had prior BRAF monotherapy can benefit from the combination, but not as many of them benefit. Perhaps I misinterpreted what Tim said. Can you shed any additional light on the advisability of trying Tafinlar + Mekinist after progressing on Zelboraf?

My black and white takeaway from that talk was that if one is about to start on BRAF therapy, then it would be better to do the BRAF/MEK combo rather than BRAF alone.

As far as any other situation, the best answer is probably to talk one's oncologist.

My black and white takeaway from that talk was that if one is about to start on BRAF therapy, then it would be better to do the BRAF/MEK combo rather than BRAF alone.

As far as any other situation, the best answer is probably to talk one's oncologist.

My black and white takeaway from that talk was that if one is about to start on BRAF therapy, then it would be better to do the BRAF/MEK combo rather than BRAF alone.

As far as any other situation, the best answer is probably to talk one's oncologist.

I have read several articles (before the last symposium) that said what POW interpreted from the wording used.  I remember one article that actually gave some breakout of statistics.  It was definately a lower % that benefited, but showed it is still worth a try, if one benefited from the Zel to try the other combo without the Zel.

I have read several articles (before the last symposium) that said what POW interpreted from the wording used.  I remember one article that actually gave some breakout of statistics.  It was definately a lower % that benefited, but showed it is still worth a try, if one benefited from the Zel to try the other combo without the Zel.

I have read several articles (before the last symposium) that said what POW interpreted from the wording used.  I remember one article that actually gave some breakout of statistics.  It was definately a lower % that benefited, but showed it is still worth a try, if one benefited from the Zel to try the other combo without the Zel.

POW    Here is the reference you cant find. The response rate for the combo of dabrafenir + mekinist after progression on another braf inhibitor is 19%. Flaherty K, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor [abstract] Pigment Cell Melanoma Res. 2011;24(1022):Abstract LBA1021–1024.

Thanks, Brent. That helped, as did the paragraph you posted here a couple of days ago (see below) that said that 19% of patients who progressed on BRAF monotherapy responded to BRAF+MEK combo therapy.

I think that the question about whether or not the combo will work for those who progressed on BRAF monotherapy is very, very important for patients and their doctors who are trying to make treatment decisions. For that reason, I just spent a couple of hours trying to track down the original articles that discuss this. As I expected, it is really, really hard to find them, but here is what I found:

1. The paragraph that Brent and I and others have seen citing 19% response rate is from a review article published in 2012. You can read it here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523565/#b107-dddt-6-391 This review article cites Flaherty et al 2011 for the info (the same citation Brent gave above). That citation is incorrect– such an abstract does not exist.

2. Flaherty et al did publish an abstract in 2011 about the combo in BRAF resistant patients. It is here http://onlinelibrary.wiley.com/doi/10.1111/j.1755-148X.2011.00909.x/pdf  It was a very preliminary study of 18 BRAF resistant patients. The data looked promising– 67% of these patients showed partial responses or stable disease but they didn't say how long these patients were followed.

3. Two years later, at the 2013 ASCO meeting, these same authors published on the same topic but this time with more patients and followed for at least 1 year. You can view that here: http://meetinglibrary.asco.org/content/112346-132  It's a rather confusing report, but the bottom line is that 63%-76% of BRAF naive patients responded to the combo and 9%-15% of BRAF resistant patients responded to the combo.  

4. I found one other report out of Australia that talked about patients who had progressed on BRAF monotherapy here: http://journals.lww.com/melanomaresearch/Abstract/publishahead/A_single_centre_experience_of_patients_with.99676.aspx Unfortunately, the abstract does not say what happened to the BRAF resistant patients and I have not been able to access the full report. These authors were primarily studying patients with brain mets. They found that 31% of patients responded to the combo, but the benefit only lasted 4-5 months. Again, these results lumped BRAF naive and BRAF resistant together.

I'm sure that this is more information than most of you need or want– I just got stubborn about trying to find an answer to my question. I included these links so that you can all read them and form your own conclusion. The bottom line for me is: 1) I can see why most melanoma oncologists now recommend starting right off with a combination of BRAF+MEK rather than a BRAF inhibitor alone, and 2) if one has progressed on BRAF monotherapy, a BRAF+ MEK combo might work, but the odds of it working are only 10% to 15%. Oh, and 3) BRAF + MEK does work on brain mets sometimes. 

Thanks, Brent. That helped, as did the paragraph you posted here a couple of days ago (see below) that said that 19% of patients who progressed on BRAF monotherapy responded to BRAF+MEK combo therapy.

I think that the question about whether or not the combo will work for those who progressed on BRAF monotherapy is very, very important for patients and their doctors who are trying to make treatment decisions. For that reason, I just spent a couple of hours trying to track down the original articles that discuss this. As I expected, it is really, really hard to find them, but here is what I found:

1. The paragraph that Brent and I and others have seen citing 19% response rate is from a review article published in 2012. You can read it here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523565/#b107-dddt-6-391 This review article cites Flaherty et al 2011 for the info (the same citation Brent gave above). That citation is incorrect– such an abstract does not exist.

2. Flaherty et al did publish an abstract in 2011 about the combo in BRAF resistant patients. It is here http://onlinelibrary.wiley.com/doi/10.1111/j.1755-148X.2011.00909.x/pdf  It was a very preliminary study of 18 BRAF resistant patients. The data looked promising– 67% of these patients showed partial responses or stable disease but they didn't say how long these patients were followed.

3. Two years later, at the 2013 ASCO meeting, these same authors published on the same topic but this time with more patients and followed for at least 1 year. You can view that here: http://meetinglibrary.asco.org/content/112346-132  It's a rather confusing report, but the bottom line is that 63%-76% of BRAF naive patients responded to the combo and 9%-15% of BRAF resistant patients responded to the combo.  

4. I found one other report out of Australia that talked about patients who had progressed on BRAF monotherapy here: http://journals.lww.com/melanomaresearch/Abstract/publishahead/A_single_centre_experience_of_patients_with.99676.aspx Unfortunately, the abstract does not say what happened to the BRAF resistant patients and I have not been able to access the full report. These authors were primarily studying patients with brain mets. They found that 31% of patients responded to the combo, but the benefit only lasted 4-5 months. Again, these results lumped BRAF naive and BRAF resistant together.

I'm sure that this is more information than most of you need or want– I just got stubborn about trying to find an answer to my question. I included these links so that you can all read them and form your own conclusion. The bottom line for me is: 1) I can see why most melanoma oncologists now recommend starting right off with a combination of BRAF+MEK rather than a BRAF inhibitor alone, and 2) if one has progressed on BRAF monotherapy, a BRAF+ MEK combo might work, but the odds of it working are only 10% to 15%. Oh, and 3) BRAF + MEK does work on brain mets sometimes. 

Thanks, Brent. That helped, as did the paragraph you posted here a couple of days ago (see below) that said that 19% of patients who progressed on BRAF monotherapy responded to BRAF+MEK combo therapy.

I think that the question about whether or not the combo will work for those who progressed on BRAF monotherapy is very, very important for patients and their doctors who are trying to make treatment decisions. For that reason, I just spent a couple of hours trying to track down the original articles that discuss this. As I expected, it is really, really hard to find them, but here is what I found:

1. The paragraph that Brent and I and others have seen citing 19% response rate is from a review article published in 2012. You can read it here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523565/#b107-dddt-6-391 This review article cites Flaherty et al 2011 for the info (the same citation Brent gave above). That citation is incorrect– such an abstract does not exist.

2. Flaherty et al did publish an abstract in 2011 about the combo in BRAF resistant patients. It is here http://onlinelibrary.wiley.com/doi/10.1111/j.1755-148X.2011.00909.x/pdf  It was a very preliminary study of 18 BRAF resistant patients. The data looked promising– 67% of these patients showed partial responses or stable disease but they didn't say how long these patients were followed.

3. Two years later, at the 2013 ASCO meeting, these same authors published on the same topic but this time with more patients and followed for at least 1 year. You can view that here: http://meetinglibrary.asco.org/content/112346-132  It's a rather confusing report, but the bottom line is that 63%-76% of BRAF naive patients responded to the combo and 9%-15% of BRAF resistant patients responded to the combo.  

4. I found one other report out of Australia that talked about patients who had progressed on BRAF monotherapy here: http://journals.lww.com/melanomaresearch/Abstract/publishahead/A_single_centre_experience_of_patients_with.99676.aspx Unfortunately, the abstract does not say what happened to the BRAF resistant patients and I have not been able to access the full report. These authors were primarily studying patients with brain mets. They found that 31% of patients responded to the combo, but the benefit only lasted 4-5 months. Again, these results lumped BRAF naive and BRAF resistant together.

I'm sure that this is more information than most of you need or want– I just got stubborn about trying to find an answer to my question. I included these links so that you can all read them and form your own conclusion. The bottom line for me is: 1) I can see why most melanoma oncologists now recommend starting right off with a combination of BRAF+MEK rather than a BRAF inhibitor alone, and 2) if one has progressed on BRAF monotherapy, a BRAF+ MEK combo might work, but the odds of it working are only 10% to 15%. Oh, and 3) BRAF + MEK does work on brain mets sometimes. 

POW    Here is the reference you cant find. The response rate for the combo of dabrafenir + mekinist after progression on another braf inhibitor is 19%. Flaherty K, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor [abstract] Pigment Cell Melanoma Res. 2011;24(1022):Abstract LBA1021–1024.

POW    Here is the reference you cant find. The response rate for the combo of dabrafenir + mekinist after progression on another braf inhibitor is 19%. Flaherty K, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor [abstract] Pigment Cell Melanoma Res. 2011;24(1022):Abstract LBA1021–1024.

Kyle, thank you for clarifying some of what you learned at the recent melanoma meeting. What you reported makes sense– it is better to start with a BRAF+Mek combo than with a BRAF inhibitor alone. I think there is compelling evidence to support that.

My question– actually a question a lot of patients here have– is if you have already progressed on a BRAF (usually Zelboraf) monotherapy will it do any good to start on Tafinlar + Mekinist? I can't seem to find any published reports about that. 

In Tim Turnham's report on the same meeting he said, "Data now shows that people who have progressed on BRAF monotherapy do not perform as well on the combination as do people who have not had prior BRAF therapy.  This suggests it is better to start with the combination." [emphasis mine] I interpreted this to mean that people who had prior BRAF monotherapy can benefit from the combination, but not as many of them benefit. Perhaps I misinterpreted what Tim said. Can you shed any additional light on the advisability of trying Tafinlar + Mekinist after progressing on Zelboraf?

Look at this thread for info:  http://forum.melanomainternational.org/mif/viewtopic.php?f=54&t=34813

Look at this thread for info:  http://forum.melanomainternational.org/mif/viewtopic.php?f=54&t=34813

Look at this thread for info:  http://forum.melanomainternational.org/mif/viewtopic.php?f=54&t=34813

Jerry    You are right on point. Defining the spinal cord issue is key to the further approach. There is data supporting adding Mekinist to the Braf inhibitor (Flaherty K, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor [abstract] Pigment Cell Melanoma Res. 2011;24(1022):Abstract LBA1021–1024.) but it would be wise to look beyond that including IL2, and Anti-Pd1.

Jerry    You are right on point. Defining the spinal cord issue is key to the further approach. There is data supporting adding Mekinist to the Braf inhibitor (Flaherty K, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor [abstract] Pigment Cell Melanoma Res. 2011;24(1022):Abstract LBA1021–1024.) but it would be wise to look beyond that including IL2, and Anti-Pd1.

Jerry    You are right on point. Defining the spinal cord issue is key to the further approach. There is data supporting adding Mekinist to the Braf inhibitor (Flaherty K, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor [abstract] Pigment Cell Melanoma Res. 2011;24(1022):Abstract LBA1021–1024.) but it would be wise to look beyond that including IL2, and Anti-Pd1.

Joy, I am very sorry that this diagnosis was confirmed. Very scary! But I have read posts from several patients who successfully fought lepto with Dr. Papadopolous at MD Anderson. I'm so glad that you have decided to contact him immediately. Excellent!

As you probably know, Nancy (Snickers60) recently gave Aldakota the run-down on her husband Wayne's success with Dr. Papas. If you didn't see it her post is here: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/update-aldakota22

In addition, Socks recently offered to use her extensive experience at MD Anderson to help other patients with questions, places to stay, etc if they have to stay in Houston for a while. Her post is here: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/md-anderson-helpadvice-if-you

If you start a new thread about leptomeningeal mets and MD Anderson, I'm sure that others will help you all they can. 

Joy, I am very sorry that this diagnosis was confirmed. Very scary! But I have read posts from several patients who successfully fought lepto with Dr. Papadopolous at MD Anderson. I'm so glad that you have decided to contact him immediately. Excellent!

As you probably know, Nancy (Snickers60) recently gave Aldakota the run-down on her husband Wayne's success with Dr. Papas. If you didn't see it her post is here: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/update-aldakota22

In addition, Socks recently offered to use her extensive experience at MD Anderson to help other patients with questions, places to stay, etc if they have to stay in Houston for a while. Her post is here: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/md-anderson-helpadvice-if-you

If you start a new thread about leptomeningeal mets and MD Anderson, I'm sure that others will help you all they can. 

Joy, I am very sorry that this diagnosis was confirmed. Very scary! But I have read posts from several patients who successfully fought lepto with Dr. Papadopolous at MD Anderson. I'm so glad that you have decided to contact him immediately. Excellent!

As you probably know, Nancy (Snickers60) recently gave Aldakota the run-down on her husband Wayne's success with Dr. Papas. If you didn't see it her post is here: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/update-aldakota22

In addition, Socks recently offered to use her extensive experience at MD Anderson to help other patients with questions, places to stay, etc if they have to stay in Houston for a while. Her post is here: http://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/md-anderson-helpadvice-if-you

If you start a new thread about leptomeningeal mets and MD Anderson, I'm sure that others will help you all they can.