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Stage III Melanoma: Adjuvant Therapy Trials

Panelists: Jeffrey S. Weber, MD, PhD, Laura and Isaac Perlmutter Cancer Center; Jason J. Luke, MD, FACP, UPMC Hillman Cancer Center; Vernon K. Sondak, MD, Moffitt Cancer Center; Ryan J. Sullivan, MD, Massachusetts General Hospital; Hussein A. Tawbi, MD, PhD
Published: Wednesday, Jul 03, 2019



Transcript:

Jeffrey S. Weber, MD, PhD:
You’ve seen the patient. The testing is in. How do the data from recent trials influence your management in the adjuvant scenario? Jason, tell us a little about the recent article in the Journal of Clinical Oncology by Dr Axel Hauschild. It was really the long-term follow-up of the COMBI-AD trial. I think they’re out to something like 4 years by now. So this is a very impressive follow-up. What does it tell you?

Jason J. Luke, MD, FACP: When we get a patient in the adjuvant setting for stage III disease, obviously we have options for both immunotherapy and targeted therapy. The targeted therapy options are based on the COMBI-AD study, which was initially presented a couple of years ago and really showed an outstanding benefit for relapse-free survival. And now we’re starting to see further updates for the longer-term follow-up of those patients.

I think they’re quite impressive results. Looking out at 3 years, we see relapse-free survival rates somewhere in the 60% range—55%, 60%—and overall survival is still trending that far. The big question is, what percentage of these patients would truly be cured with targeted therapy? There’s sort of a hypothesis that we’re suppressing things. Are we truly eliminating those cells?

And these publications, the previous presentation, make a case that, in fact, there is a subset of patients who are truly being cured out with this longer-term follow-up.

Jeffrey S. Weber, MD, PhD: That’s the so-called cure rate model. Is that what you’re referring to?

Jason J. Luke, MD, FACP: Exactly. So projecting out, looking at the slope of these curves of both the combination dabrafenib-trametinib versus the placebos, we’re starting to see this absolute benefit being stable between the curves—somewhere in the mid-50s versus high-30s sort of range—really suggesting there is a 10% or higher absolute cure rate there. And I think that’s quite powerful when we think about adjuvant therapy for these patients who really are at high risk of recurrence.

Jeffrey S. Weber, MD, PhD: Yeah. There will be a few other abstracts, though not necessarily looking at long-term results of adjuvant studies. The nice thing about COMBI-AD is it was started before any of the other studies, so it probably has the longest follow-up, which is important. But I think there will be a poster presentation reviewing immune-related adverse events and association, or I should say lack thereof, of the immune-related adverse events with relapse-free survival in CheckMate 238, which was the nivolumab-versus-ipilimumab adjuvant study.

It interests me that even though the urban legend is that the immune-related adverse events may be associated with outcome, at least in the study there really wasn’t much a potent association of any of the different types of immune-related adverse events. And this is now 900 patients. There has been no association with relapse-free survival that was statistically significant.

I did not see it, but I hear that there was a poster that described some similar data from the less mature KEYNOTE-054 study, there was some thought that there was some association of immune-related adverse events with relapse-free survival. It would be yet another argument over how you reconcile those data. But at the end of the day, when patients ask me, “Well, if I don’t get adverse effects, does that mean it’s not working?” I tell them, “No, I wouldn’t think that way.” Do you get that question?

Jason J. Luke, MD, FACP: Yes, and I think this all dates back to the beginning of the checkpoint blockade. And obviously with ipilimumab, alone, there’s sort of this question of, is it or is it not adverse-effect related? We can’t confidently say that it is.

Jeffrey S. Weber, MD, PhD: Yeah, to me it’s weak.

Jason J. Luke, MD, FACP: The patients will either do well or not. I don’t think this is the thing we should focus on.

Jeffrey S. Weber, MD, PhD: Ryan, do you get that answer also?

Ryan J. Sullivan, MD: Yeah, I get that question asked quite frequently, and I agree. I think there may be some toxicities that seemingly are associated with benefit, like vitiligo, which makes sense. We’re treating melanoma, and vitiligo is the immune system’s attack on benign melanocytes. I think that probably does associate with benefit, but colitis or pneumonitis or hepatitis, I think we get…

Hussein A. Tawbi, MD, PhD: It’s really interesting that you kind of discuss whether more toxic-treatments should be more effective. At this ASCO [American Society of Clinical Oncology Annual] Meeting, the results from E1609 are going to presented. This is a randomized multicentered trial that includes over 1600 patients in the United States. It compared ipilimumab with what was the only standard of care at the time, which was high-dose interferon. And interestingly, in that study, they actually had 2 different arms with 2 different doses of ipilimumab. It was 3 mg/kg for 1 arm and then 10 mg/kg for 1 arm.

Let’s speak of things that can cause more toxicity. Ipilimumab at 10 mg/kg actually had a grade 3 and 4 rate of adverse events that was almost 50%. Whereas the 3-mg/kg dose only had a 37% rate. I mean, this is still significant. This is a large number, but it is a lot less than the 10-mg/kg rate. And yet when you looked at efficacy, and that’s what is being reported on at this particular ASCO meeting, the higher dose wasn’t associated with a higher efficacy against interferon.

Jeffrey S. Weber, MD, PhD: In fact, it almost looked as if the lower dose was a little bit better. I mean, did I misinterpret those data?

Hussein A. Tawbi, MD, PhD: No, you’re right on. In fact, the hazard ratio for the 3-mg/kg dose was actually 0.78, whereas for the 10-mg/kg dose, it was actually 0.82. So it kind of looked less effective. You can’t directly compare because they weren’t actually compared against each other. They were all beating up interferon. The interesting part that I find from this particular trial as well is that this was an overall survival reported for this particular study. There was enough of a follow-up that there were some overall survival data indicating that ipilimumab may be more effective than high-dose interferon in affecting overall survival. But again, it’s a modest improvement from my perspective. Now that we have nivolumab clearly being superior to ipilimumab in this setting, even to the 10-mg/kg dose in CheckMate 238, I think this particular study doesn’t directly impact practices.

Jeffrey S. Weber, MD, PhD: Ryan, tell us about KEYNOTE-054, because that’s the most recent adjuvant study with data. Again, relapse-free survival. No overall survival yet, but tell us. That was recently published.

Ryan J. Sullivan, MD: It was. It actually builds on another question that I’m asked frequently: “Do I need to be treated now, or can I be treated when I progress or relapse if I relapse?” It’s a reasonable question. If the patient has a 50% chance of relapse, that means they have a 50% chance of being cured with Dr Vernon Sondak’s or his colleague’s surgery. And so the questions that are being asked in KEYNOTE-054 are 2-fold.

One: Is giving pembrolizumab better than giving placebo in the postoperative setting for stage III melanoma? And what’s clear from a relapse-free survival standpoint is that it absolutely is. It’s associated with a much lower relapse rate. The hazard ratio is 0.54. So about half of patients will relapse when they’re treated with pembrolizumab versus placebo. At time of relapse, patients are offered the chance to have pembrolizumab and will be followed further. And so does pembrolizumab reduce relapse? Yes. So the first question has been answered.

And the second question is, does getting pembrolizumab right after surgery, or monitoring closely after the surveillance, and then at progression, or relapse, and then being treated with pembrolizumab, does that actually impact overall survival? Does it really matter? It’s an interesting question. It’s the only trial that’s been designed to answer that question. And what I tell my patients is, “I don’t know.”

Jeffrey S. Weber, MD, PhD: Would you feel comfortable, as a patient going on that sort of trial? It would be with the idea of, “Well, you can get pembrolizumab now, or maybe you can get it later when you’re relapsed.”

Ryan J. Sullivan, MD: At the time, the trial was perfectly OK. But the standard of care was arguably placebo or observation.

Jeffrey S. Weber, MD, PhD: Understood.

Ryan J. Sullivan, MD: And so, at this day and age, I think it does allow us to have conversations with patients who we think might have a bit more risk—say, a patient with an autoimmune condition but a high-risk melanoma. Should I treat that person now and risk their autoimmune toxicity flare now, or do I follow them very closely? And then if they are a recurrent patient, do I then treat them?

Vernon K. Sondak, MD: For earlier-stage disease, that exact question—treat everybody now versus selectively treating only those who recurred—is going to be an extraordinarily important question.

Jason J. Luke, MD, FACP: And then, along those lines, clinical trials are starting to explore stage II disease. They have been historically considered as lower risk, but in fact, actually, yes, there is some substantial risk there. So questions will become quite pressing. But just to summarize quickly, I think it’s really important to clearly state that the days of interferon and ipilimumab have really now passed, in terms of stage III disease. It really should only be PD-1 [programmed cell death protein 1] antibodies or BRAF in that setting. We still sometimes get referrals of patients who are started on some of these things because they are listed in compendium guidelines, but I really emphasize that’s really not a reasonable standard of care at this point.


Transcript Edited for Clarity

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Transcript:

Jeffrey S. Weber, MD, PhD:
You’ve seen the patient. The testing is in. How do the data from recent trials influence your management in the adjuvant scenario? Jason, tell us a little about the recent article in the Journal of Clinical Oncology by Dr Axel Hauschild. It was really the long-term follow-up of the COMBI-AD trial. I think they’re out to something like 4 years by now. So this is a very impressive follow-up. What does it tell you?

Jason J. Luke, MD, FACP: When we get a patient in the adjuvant setting for stage III disease, obviously we have options for both immunotherapy and targeted therapy. The targeted therapy options are based on the COMBI-AD study, which was initially presented a couple of years ago and really showed an outstanding benefit for relapse-free survival. And now we’re starting to see further updates for the longer-term follow-up of those patients.

I think they’re quite impressive results. Looking out at 3 years, we see relapse-free survival rates somewhere in the 60% range—55%, 60%—and overall survival is still trending that far. The big question is, what percentage of these patients would truly be cured with targeted therapy? There’s sort of a hypothesis that we’re suppressing things. Are we truly eliminating those cells?

And these publications, the previous presentation, make a case that, in fact, there is a subset of patients who are truly being cured out with this longer-term follow-up.

Jeffrey S. Weber, MD, PhD: That’s the so-called cure rate model. Is that what you’re referring to?

Jason J. Luke, MD, FACP: Exactly. So projecting out, looking at the slope of these curves of both the combination dabrafenib-trametinib versus the placebos, we’re starting to see this absolute benefit being stable between the curves—somewhere in the mid-50s versus high-30s sort of range—really suggesting there is a 10% or higher absolute cure rate there. And I think that’s quite powerful when we think about adjuvant therapy for these patients who really are at high risk of recurrence.

Jeffrey S. Weber, MD, PhD: Yeah. There will be a few other abstracts, though not necessarily looking at long-term results of adjuvant studies. The nice thing about COMBI-AD is it was started before any of the other studies, so it probably has the longest follow-up, which is important. But I think there will be a poster presentation reviewing immune-related adverse events and association, or I should say lack thereof, of the immune-related adverse events with relapse-free survival in CheckMate 238, which was the nivolumab-versus-ipilimumab adjuvant study.

It interests me that even though the urban legend is that the immune-related adverse events may be associated with outcome, at least in the study there really wasn’t much a potent association of any of the different types of immune-related adverse events. And this is now 900 patients. There has been no association with relapse-free survival that was statistically significant.

I did not see it, but I hear that there was a poster that described some similar data from the less mature KEYNOTE-054 study, there was some thought that there was some association of immune-related adverse events with relapse-free survival. It would be yet another argument over how you reconcile those data. But at the end of the day, when patients ask me, “Well, if I don’t get adverse effects, does that mean it’s not working?” I tell them, “No, I wouldn’t think that way.” Do you get that question?

Jason J. Luke, MD, FACP: Yes, and I think this all dates back to the beginning of the checkpoint blockade. And obviously with ipilimumab, alone, there’s sort of this question of, is it or is it not adverse-effect related? We can’t confidently say that it is.

Jeffrey S. Weber, MD, PhD: Yeah, to me it’s weak.

Jason J. Luke, MD, FACP: The patients will either do well or not. I don’t think this is the thing we should focus on.

Jeffrey S. Weber, MD, PhD: Ryan, do you get that answer also?

Ryan J. Sullivan, MD: Yeah, I get that question asked quite frequently, and I agree. I think there may be some toxicities that seemingly are associated with benefit, like vitiligo, which makes sense. We’re treating melanoma, and vitiligo is the immune system’s attack on benign melanocytes. I think that probably does associate with benefit, but colitis or pneumonitis or hepatitis, I think we get…

Hussein A. Tawbi, MD, PhD: It’s really interesting that you kind of discuss whether more toxic-treatments should be more effective. At this ASCO [American Society of Clinical Oncology Annual] Meeting, the results from E1609 are going to presented. This is a randomized multicentered trial that includes over 1600 patients in the United States. It compared ipilimumab with what was the only standard of care at the time, which was high-dose interferon. And interestingly, in that study, they actually had 2 different arms with 2 different doses of ipilimumab. It was 3 mg/kg for 1 arm and then 10 mg/kg for 1 arm.

Let’s speak of things that can cause more toxicity. Ipilimumab at 10 mg/kg actually had a grade 3 and 4 rate of adverse events that was almost 50%. Whereas the 3-mg/kg dose only had a 37% rate. I mean, this is still significant. This is a large number, but it is a lot less than the 10-mg/kg rate. And yet when you looked at efficacy, and that’s what is being reported on at this particular ASCO meeting, the higher dose wasn’t associated with a higher efficacy against interferon.

Jeffrey S. Weber, MD, PhD: In fact, it almost looked as if the lower dose was a little bit better. I mean, did I misinterpret those data?

Hussein A. Tawbi, MD, PhD: No, you’re right on. In fact, the hazard ratio for the 3-mg/kg dose was actually 0.78, whereas for the 10-mg/kg dose, it was actually 0.82. So it kind of looked less effective. You can’t directly compare because they weren’t actually compared against each other. They were all beating up interferon. The interesting part that I find from this particular trial as well is that this was an overall survival reported for this particular study. There was enough of a follow-up that there were some overall survival data indicating that ipilimumab may be more effective than high-dose interferon in affecting overall survival. But again, it’s a modest improvement from my perspective. Now that we have nivolumab clearly being superior to ipilimumab in this setting, even to the 10-mg/kg dose in CheckMate 238, I think this particular study doesn’t directly impact practices.

Jeffrey S. Weber, MD, PhD: Ryan, tell us about KEYNOTE-054, because that’s the most recent adjuvant study with data. Again, relapse-free survival. No overall survival yet, but tell us. That was recently published.

Ryan J. Sullivan, MD: It was. It actually builds on another question that I’m asked frequently: “Do I need to be treated now, or can I be treated when I progress or relapse if I relapse?” It’s a reasonable question. If the patient has a 50% chance of relapse, that means they have a 50% chance of being cured with Dr Vernon Sondak’s or his colleague’s surgery. And so the questions that are being asked in KEYNOTE-054 are 2-fold.

One: Is giving pembrolizumab better than giving placebo in the postoperative setting for stage III melanoma? And what’s clear from a relapse-free survival standpoint is that it absolutely is. It’s associated with a much lower relapse rate. The hazard ratio is 0.54. So about half of patients will relapse when they’re treated with pembrolizumab versus placebo. At time of relapse, patients are offered the chance to have pembrolizumab and will be followed further. And so does pembrolizumab reduce relapse? Yes. So the first question has been answered.

And the second question is, does getting pembrolizumab right after surgery, or monitoring closely after the surveillance, and then at progression, or relapse, and then being treated with pembrolizumab, does that actually impact overall survival? Does it really matter? It’s an interesting question. It’s the only trial that’s been designed to answer that question. And what I tell my patients is, “I don’t know.”

Jeffrey S. Weber, MD, PhD: Would you feel comfortable, as a patient going on that sort of trial? It would be with the idea of, “Well, you can get pembrolizumab now, or maybe you can get it later when you’re relapsed.”

Ryan J. Sullivan, MD: At the time, the trial was perfectly OK. But the standard of care was arguably placebo or observation.

Jeffrey S. Weber, MD, PhD: Understood.

Ryan J. Sullivan, MD: And so, at this day and age, I think it does allow us to have conversations with patients who we think might have a bit more risk—say, a patient with an autoimmune condition but a high-risk melanoma. Should I treat that person now and risk their autoimmune toxicity flare now, or do I follow them very closely? And then if they are a recurrent patient, do I then treat them?

Vernon K. Sondak, MD: For earlier-stage disease, that exact question—treat everybody now versus selectively treating only those who recurred—is going to be an extraordinarily important question.

Jason J. Luke, MD, FACP: And then, along those lines, clinical trials are starting to explore stage II disease. They have been historically considered as lower risk, but in fact, actually, yes, there is some substantial risk there. So questions will become quite pressing. But just to summarize quickly, I think it’s really important to clearly state that the days of interferon and ipilimumab have really now passed, in terms of stage III disease. It really should only be PD-1 [programmed cell death protein 1] antibodies or BRAF in that setting. We still sometimes get referrals of patients who are started on some of these things because they are listed in compendium guidelines, but I really emphasize that’s really not a reasonable standard of care at this point.


Transcript Edited for Clarity
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