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Sequencing Dual BRAF-MEK Inhibition and Immunotherapy

Panelists:Keith T. Flaherty, MD, Massachusetts General Hospital; Rene Gonzalez, MD, University of Colorado Melanoma Research Clinics; Jason J. Luke, MD, FACP, University of Chicago Medicine; Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center
Published: Tuesday, Feb 09, 2016


Transcript:

Keith Flaherty, MD:
I wanted to go to this issue of wanting to get the therapies to patients when they have the lowest disease burden, being true for targeted therapy and immune therapy. Jason, in your practice, if you have a patient who’s had the ipilimumab/nivolumab combination, who could only have been patients who were coming off trials for the most part, what’s your threshold in terms of BRAF mutation? How much are you willing to let a little bit of progression on a scan kind of be followed versus a quick trigger to move to targeted therapy?

Jason Luke, MD, FACP: I have a low threshold. There is this phenomenon of pseudoprogression with immune checkpoint–blocking antibodies. Perhaps with ipilimumab it’s 10% to 15%. It’s about the same or maybe less with anti-PD-1 antibodies. I think for a patient that’s in front of me, I don’t really care. I want that patient to do well over time. If it turns out that he or she gets a big response, and there was antecedent immune checking–blocking antibody, six months from now we can then stop the targeted therapies, and if they’re stable then, who cares.

Following patients for pseudoprogression? I’m not excited about doing that particularly. The other thing I would throw in is that in a lot of my patients, I use BRAF/MEK inhibitor combination therapy as the backbone. I know I can always go to it. And so if patients come off of other things, we’re going to go back to it, get this back under control for a few months, and then we can think what else can we try to do.

What is another trial that we can try to get them to, especially in the context of brain metastases? So that is another very powerful strategy, and we didn’t touch on this in the context of radiation. But my preference in most BRAF-mutant patients who have more than one or two lesions is a BRAF/MEK inhibitor as opposed to radiation therapy.

Keith Flaherty, MD: It’s an interesting point. The idea that you actually use drug therapy over any form of radiation therapy in melanoma is kind of an unexpected consequence of where we are in the field, but it seems to be true. Rene, you were talking about this issue of a lead-in of targeted therapy before. Since you’ve got a whole portfolio of patients in your practice and many viewers of this program may have just a handful, who are the patients? Where do you draw the line? Is this just for high disease–burden symptomatic patients, elevated LDH, that end of the spectrum where you would contemplate that?

Rene Gonzalez, MD: Think of switching?

Keith Flaherty, MD: Yeah. In other words, where you feel the imperative to start with targeted therapy but a consideration of switching.

Rene Gonzalez, MD: Before the combination, I wasn’t particularly enthusiastic about switching because the response rate to ipilimumab is low. But, again, it gets us that long tail to the curve. But with the advent of combination immunotherapy, it’s come into my mind more often, should I be switching this patient? And I think my bar is falling as to when I do that because with the BRAF/MEK combination, half the patients with the BRAF/MEK combination will die in about two years. And so I’m not worried about the half that go beyond that, but it’s the front end of that curve that we might be able to impact better now rather than later.

Keith Flaherty, MD: Right, fair enough. Maybe just briefly summarize since we’ve seen some updated data at this SMR meeting on the vemurafenib/cobimetinib combination that was just approved. How would you just quickly score response rate, median progression-free survival for the two BRAF/MEK combos out there? Overall survival landmarks? When you’re talking to patients about what those therapies can offer, what kind of numbers are in your mind there?

Rene Gonzalez, MD: In terms of the median survival, it’s about two years, 24, 25, 26 months, something like that. The progression-free survival for the single-agent BRAF inhibitors is in the range of six to seven months. With the combination, the progression-free survival is a little over a year probably. And so at two years, half the patients are alive. At three years, it’s somewhat less than that, but hopefully those curves will continue to show that some of those patients hopefully can be long-term survivors. But it’s the rapid progressors, once you start, that are the most problematic. And they tend to be the patients with the most tumor, but not always. Sometimes patients with a big, bulky tumor will have a durable long-term response of years.

Jeffrey Weber, MD, PhD: But I think those are the patients where you should give an induction regimen of BRAF plus MEK. The data from Jennifer Wargo and Georgina Long suggest that, immunologically speaking, if you’re going to give them an induction dose or regimen, you should only do it for six to eight weeks. By the time six to eight weeks has elapsed, that initial burst of lymphocytes that gets into the tumor as a result of the initial tumor regression is gone. And my gut tells me, and it’s based on some data, that as you can continue to give BRAF plus MEK, especially to the rapid progressors who you know are going to be the ones who do poorly, they are going to be developing not only resistance to BRAF/MEK, but they become immune-resistant and develop cold tumors.

So, if you’re going to take advantage of the data that Jennifer Wargo at MD Anderson has shown, giving the BRAF/MEK drugs early on gives you that influx of T cells making a cold tumor into a hot one. I’m thinking of doing six to eight weeks of treatment and then quitting with BRAF/MEK and immediately going to probably the combination, since this was a patient who had aggressive disease in the first place. There’s no trial to support that. I’m not sure that there ever will be a trial to support it, but I think it’s an idea that should be considered.

Jason Luke, MD, FACP: You just have to note that the current FDA label for the combination of ipilimumab and nivolumab is specifically for BRAF wild-type patients. So, if you were going to stay on label, you actually probably shouldn’t do that just yet. So, despite the fact that I think we all agree with what you just said, that is a caveat. I guess I’m struck by a couple of comments around some of the things that people have said.

Definitely there is a population of patients who stay on BRAF/MEK combinations for a long time, and I think from the COMBI-V, COMBI-D, and the coBRIM study, it looks like it’s a third of patients that a couple of years out are still on those drugs. And Georgina presented at the SMR conference clinical aspects of patients who go out a long time and really drill down on the point that it’s patients who are good performance status and low LDH who are most likely to be on drug for a long period of time. And that is something we need to go back and think about. Because we have this idea that, oh, those patients are the ones that have to get immunotherapy. And I don’t know how we’re going to select those people yet, but certainly it’s something we need to really think back upon.

Keith Flaherty, MD: Right.

Jeffrey Weber, MD, PhD: But this idea that you’re only going to use those drugs in the BRAF wild-type population I think is, shall we say, more honored in the breach than in the observance, as Shakespeare would say so, for the immunotherapy. But a lot of docs, including me, are treating mutated patients with the combination regimen. I’m not saying you should do it in place of BRAF/MEK, but it is certainly an option that I’ve taken advantage of.

Keith Flaherty, MD: True.

Jason Luke, MD, FACP: The other thing that I’ll note is that there was a great paper by Roger Lowe’s group, with Antoni Ribas, looking at nongenomic mechanisms of resistance to BRAF/MEK-targeted therapies. And that paper clearly showed at least a quarter of the resistance that develops to combination therapy is immunologically driven. It’s this concept that whatever the inflammatory infiltrate is is lost. And I think that we’ve seen that. If we do on-treatment biopsies after initiation of a BRAF-inhibitor combination, you seen an initial influx of CD8 T cells, and that’s lost at progression. And so it very well could be that treating all the way to progression actually could kill the immune response.

Jeffrey Weber, MD, PhD: Oh, I agree.

Jason Luke, MD, FACP: And I think this actually has implications on multiple combinations going forward. We probably shouldn’t be in a situation of overlapping all of these treatments—BRAF, MEK, PD-1—all at the same time because it may be that one may actually have a detrimental impact on another. And we actually have laboratory data that suggest that we may mechanistically figure out why.

Jeffrey Weber, MD, PhD: That’s why I think you should give that brief burst of BRAF/MEK, take advantage of the lack of immunologic resistance and MAP kinase resistance, and then quickly move on to the immunotherapy. But will there be a trial to test that? There could be. It could simply be a randomized phase II of, say, dabrafenib plus trametinib continuous therapy versus dabrafenib plus trametinib six weeks, stop, ipilimumab plus nivolumab. Will that trial happen? I don’t know. That’s the kind of trial the Cooperative Groups ought to do, and I like the idea.

Keith Flaherty, MD: Let me make a cautionary note first, which I think you’ve all touched on. I’d say we all agree that combination targeted immunotherapy in practice right now is not quite ready for prime time. These sequences and how close to put the drugs together, when to make that switch, are real-world issues. And even absent of a clinical trial, we’re all facing patients where we feel like we need to do something to try to optimize their long-term outcome by weaving these therapies in a regimen that puts them next to each other but not overlapping.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
I wanted to go to this issue of wanting to get the therapies to patients when they have the lowest disease burden, being true for targeted therapy and immune therapy. Jason, in your practice, if you have a patient who’s had the ipilimumab/nivolumab combination, who could only have been patients who were coming off trials for the most part, what’s your threshold in terms of BRAF mutation? How much are you willing to let a little bit of progression on a scan kind of be followed versus a quick trigger to move to targeted therapy?

Jason Luke, MD, FACP: I have a low threshold. There is this phenomenon of pseudoprogression with immune checkpoint–blocking antibodies. Perhaps with ipilimumab it’s 10% to 15%. It’s about the same or maybe less with anti-PD-1 antibodies. I think for a patient that’s in front of me, I don’t really care. I want that patient to do well over time. If it turns out that he or she gets a big response, and there was antecedent immune checking–blocking antibody, six months from now we can then stop the targeted therapies, and if they’re stable then, who cares.

Following patients for pseudoprogression? I’m not excited about doing that particularly. The other thing I would throw in is that in a lot of my patients, I use BRAF/MEK inhibitor combination therapy as the backbone. I know I can always go to it. And so if patients come off of other things, we’re going to go back to it, get this back under control for a few months, and then we can think what else can we try to do.

What is another trial that we can try to get them to, especially in the context of brain metastases? So that is another very powerful strategy, and we didn’t touch on this in the context of radiation. But my preference in most BRAF-mutant patients who have more than one or two lesions is a BRAF/MEK inhibitor as opposed to radiation therapy.

Keith Flaherty, MD: It’s an interesting point. The idea that you actually use drug therapy over any form of radiation therapy in melanoma is kind of an unexpected consequence of where we are in the field, but it seems to be true. Rene, you were talking about this issue of a lead-in of targeted therapy before. Since you’ve got a whole portfolio of patients in your practice and many viewers of this program may have just a handful, who are the patients? Where do you draw the line? Is this just for high disease–burden symptomatic patients, elevated LDH, that end of the spectrum where you would contemplate that?

Rene Gonzalez, MD: Think of switching?

Keith Flaherty, MD: Yeah. In other words, where you feel the imperative to start with targeted therapy but a consideration of switching.

Rene Gonzalez, MD: Before the combination, I wasn’t particularly enthusiastic about switching because the response rate to ipilimumab is low. But, again, it gets us that long tail to the curve. But with the advent of combination immunotherapy, it’s come into my mind more often, should I be switching this patient? And I think my bar is falling as to when I do that because with the BRAF/MEK combination, half the patients with the BRAF/MEK combination will die in about two years. And so I’m not worried about the half that go beyond that, but it’s the front end of that curve that we might be able to impact better now rather than later.

Keith Flaherty, MD: Right, fair enough. Maybe just briefly summarize since we’ve seen some updated data at this SMR meeting on the vemurafenib/cobimetinib combination that was just approved. How would you just quickly score response rate, median progression-free survival for the two BRAF/MEK combos out there? Overall survival landmarks? When you’re talking to patients about what those therapies can offer, what kind of numbers are in your mind there?

Rene Gonzalez, MD: In terms of the median survival, it’s about two years, 24, 25, 26 months, something like that. The progression-free survival for the single-agent BRAF inhibitors is in the range of six to seven months. With the combination, the progression-free survival is a little over a year probably. And so at two years, half the patients are alive. At three years, it’s somewhat less than that, but hopefully those curves will continue to show that some of those patients hopefully can be long-term survivors. But it’s the rapid progressors, once you start, that are the most problematic. And they tend to be the patients with the most tumor, but not always. Sometimes patients with a big, bulky tumor will have a durable long-term response of years.

Jeffrey Weber, MD, PhD: But I think those are the patients where you should give an induction regimen of BRAF plus MEK. The data from Jennifer Wargo and Georgina Long suggest that, immunologically speaking, if you’re going to give them an induction dose or regimen, you should only do it for six to eight weeks. By the time six to eight weeks has elapsed, that initial burst of lymphocytes that gets into the tumor as a result of the initial tumor regression is gone. And my gut tells me, and it’s based on some data, that as you can continue to give BRAF plus MEK, especially to the rapid progressors who you know are going to be the ones who do poorly, they are going to be developing not only resistance to BRAF/MEK, but they become immune-resistant and develop cold tumors.

So, if you’re going to take advantage of the data that Jennifer Wargo at MD Anderson has shown, giving the BRAF/MEK drugs early on gives you that influx of T cells making a cold tumor into a hot one. I’m thinking of doing six to eight weeks of treatment and then quitting with BRAF/MEK and immediately going to probably the combination, since this was a patient who had aggressive disease in the first place. There’s no trial to support that. I’m not sure that there ever will be a trial to support it, but I think it’s an idea that should be considered.

Jason Luke, MD, FACP: You just have to note that the current FDA label for the combination of ipilimumab and nivolumab is specifically for BRAF wild-type patients. So, if you were going to stay on label, you actually probably shouldn’t do that just yet. So, despite the fact that I think we all agree with what you just said, that is a caveat. I guess I’m struck by a couple of comments around some of the things that people have said.

Definitely there is a population of patients who stay on BRAF/MEK combinations for a long time, and I think from the COMBI-V, COMBI-D, and the coBRIM study, it looks like it’s a third of patients that a couple of years out are still on those drugs. And Georgina presented at the SMR conference clinical aspects of patients who go out a long time and really drill down on the point that it’s patients who are good performance status and low LDH who are most likely to be on drug for a long period of time. And that is something we need to go back and think about. Because we have this idea that, oh, those patients are the ones that have to get immunotherapy. And I don’t know how we’re going to select those people yet, but certainly it’s something we need to really think back upon.

Keith Flaherty, MD: Right.

Jeffrey Weber, MD, PhD: But this idea that you’re only going to use those drugs in the BRAF wild-type population I think is, shall we say, more honored in the breach than in the observance, as Shakespeare would say so, for the immunotherapy. But a lot of docs, including me, are treating mutated patients with the combination regimen. I’m not saying you should do it in place of BRAF/MEK, but it is certainly an option that I’ve taken advantage of.

Keith Flaherty, MD: True.

Jason Luke, MD, FACP: The other thing that I’ll note is that there was a great paper by Roger Lowe’s group, with Antoni Ribas, looking at nongenomic mechanisms of resistance to BRAF/MEK-targeted therapies. And that paper clearly showed at least a quarter of the resistance that develops to combination therapy is immunologically driven. It’s this concept that whatever the inflammatory infiltrate is is lost. And I think that we’ve seen that. If we do on-treatment biopsies after initiation of a BRAF-inhibitor combination, you seen an initial influx of CD8 T cells, and that’s lost at progression. And so it very well could be that treating all the way to progression actually could kill the immune response.

Jeffrey Weber, MD, PhD: Oh, I agree.

Jason Luke, MD, FACP: And I think this actually has implications on multiple combinations going forward. We probably shouldn’t be in a situation of overlapping all of these treatments—BRAF, MEK, PD-1—all at the same time because it may be that one may actually have a detrimental impact on another. And we actually have laboratory data that suggest that we may mechanistically figure out why.

Jeffrey Weber, MD, PhD: That’s why I think you should give that brief burst of BRAF/MEK, take advantage of the lack of immunologic resistance and MAP kinase resistance, and then quickly move on to the immunotherapy. But will there be a trial to test that? There could be. It could simply be a randomized phase II of, say, dabrafenib plus trametinib continuous therapy versus dabrafenib plus trametinib six weeks, stop, ipilimumab plus nivolumab. Will that trial happen? I don’t know. That’s the kind of trial the Cooperative Groups ought to do, and I like the idea.

Keith Flaherty, MD: Let me make a cautionary note first, which I think you’ve all touched on. I’d say we all agree that combination targeted immunotherapy in practice right now is not quite ready for prime time. These sequences and how close to put the drugs together, when to make that switch, are real-world issues. And even absent of a clinical trial, we’re all facing patients where we feel like we need to do something to try to optimize their long-term outcome by weaving these therapies in a regimen that puts them next to each other but not overlapping.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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