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Adjuvant Therapy for Patients with Melanoma

Panelists: Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center; Robert H. I. Andtbacka, MD, CM, Huntsman Cancer Institute; Georgina Long, MD, PhD, Melanoma Institute of Australia at the University of Sydney; Michael A. Davies, MD, PhD, University of Texas MD Anderson Cancer Center; Jason J. Luke, MD, University of Chicago
Published: Monday, Jul 10, 2017



Transcript:

Jeffrey S. Weber, MD, PhD:
Jason, who do you decide to treat on drugs like adjuvant ipilimumab, which has been approved in the United States for over a year at 10 mg/kg, which is a significant dose—who do you decide to treat with that?

Jason J. Luke, MD: It’s obviously a difficult conversation. When we look at the data set from the EORTC 18071 study, the study included all stage 3 disease population, and that is the approved group of patients who could get ipilimumab. Now, in clinical practice, I find it’s a much more fraught conversation. I would say that I absolutely treat patients with ipilimumab if I have that sense from clinic that they have a high likelihood of recurrence, and that can be informed by several factors. But the point I will make is that, coming on after the discussion around completion lymph node dissection, there’s a substantial population of patients with low volume, single-node metastasis—those are absolutely the patients I would not treat with ipilimumab, where I think the likelihood of recurrence is actually quite low, and therefore the toxicity profile of giving the drug in the adjuvant setting is not justified.

Jeffrey S. Weber, MD, PhD: Although, interestingly, you could think about it the other way. You could think, “Well, we’re not doing the completion lymphadenectomy. I’m putting them at a little more risk of locoregional recurrence”—which I suspect we’ll find in MSLT-2—“maybe those are the people I should treat with adjuvant therapy.”

Jason J. Luke, MD: But if you look into the forest plots in the study, the actual benefit in terms of survival was relatively modest, if not nil, in the stage 3A population.

Georgina Long, MD, PhD: Jason, you’re not talking about the trial that was presented today, but you’re talking about the placebo versus 10 mg/kg study, which showed a hazard ratio of 0.72. That’s actually a nearly 30% risk reduction in death, which is an absolute benefit of 10%.

Jason J. Luke, MD: That was in the all-stage-3 population, though. And, if you look at the substages that drove most of that benefit, very little of it was from stage 3A.

Michael A. Davies, MD, PhD: One of the caveats to that trial, though, when I look at it, is the fact that in the patients who were on the placebo arm and recurred, it was actually a very small percentage of them who actually went on to receive ipilimumab for stage 4 disease, which we know can also have a survival benefit. So, I think there is some challenge to interpreting the results of that study.

Georgina Long, MD, PhD: In Australia, we don’t have ipilimumab 10 mg reimbursed, but even if we did, one of the things that we discuss with patients who are considering ipilimumab is, “Well, we don’t actually know whether or not waiting until you have stage 4 disease and treating with our best upfront Rolls Royce treatment is better for you,” because that trial was conducted around 2008, when we had no therapies available.

Jeffrey S. Weber, MD, PhD: True, but that’s a tough discussion, I must say. Let’s digress for a second. We heard a terrific talk today from Ahmad Tarhini from the University of Pittsburgh about early data from the ECOG-ACRIN 1609 study, which was a randomized, very large cooperative group study for patients with resected high-risk melanoma. It gave ipilimumab at a 3 mg/kg dose, ipilimumab at a 10 mg/kg dose, or high-dose interferon. It’s a study that has had at least 3 years of follow-up in almost all patients. Jason, what am I supposed to tell my patients based on those data? Could I safely tell patients, “Oh, no, you shouldn’t get 10 mg/kg, you should get 3 mg/kg.” What do you tell your patients?

Jason J. Luke, MD: Well, I haven’t told any of them yet, but what I plan to discuss with them is that it’s quite clear that the toxicity is increased with the higher dose—but that has been known. I actually have to say that I feel like we still need to take a bit of a cautious approach to these data. I think we all want to rush to the conclusion that they’re equivalent, and therefore, we can reduce the toxicity for patients. But there is also a study in the metastatic setting that shows there’s an increased survival advantage to giving the higher dose. So, in thinking about these data so far, I still haven’t been convinced that I would not treat patients in the adjuvant setting with 10 mg/kg, and I think that that does remain the standard of care until we really, truly see the readouts from that study with longer-term follow-up.

Georgina Long, MD, PhD: I couldn’t agree more, particularly when you look at the stage 4 patients in the trial and you see that the progression-free survival in the 3 mg/kg versus 10 mg/kg setting—this is for metastatic disease—shows no difference, yet we see a 10% overall survival benefit. So, here, we’ve just seen early data on the relapse-free survival. And we know for stage 3 melanoma that sometimes you don’t start to see separation in survival curves for 2 or 3 years, which is one of the problems with the DeCOG completion lymph node dissection trial.

Jeffrey S. Weber, MD, PhD: It sounds like there’s a little controversy. Let’s hear from Mike, and then let’s hear from Robert. Would you offer your patients 3 mg/kg based on the virtually identical 3-year relapse-free survival rates in that ECOG 1609 study? Or are you going to go with the standard, well-tested, 10 mg/kg treatment with a 40% rate of grade 3/4 immune-related adverse events?

Michael A. Davies, MD, PhD: I think, actually, we usually choose door C. At this point, for our patients in the adjuvant setting, we are really trying to get them onto clinical trials. I think that we’ve seen a complete revolution in the way we treat patients with stage 4 disease over the last 5 to 7 years. I anticipate that we’re similarly going to revolutionize adjuvant therapy. Really, what we try to do as often as possible is find clinical trials for patients to go on. In terms of directly answering your question, if you only have doors A and B, I agree at this point—I don’t think we’re ready to change the recommendation for adjuvant treatment to the 3 mg/kg dose, but I do think it was quite striking how overlapping the relapse-free survival curves were at this initial point in time. So, certainly, we’ll need close follow-up in terms of what the maturing results from the study are.

Jeffrey S. Weber, MD, PhD: The final aspect of this question is, Robert, you have to make the decision. You’re the PI of the next adjuvant trial of regimen X versus regimen Y versus ipilimumab, which is the standard of care. You can choose ipilimumab at 10 mg/kg or ipilimumab at 3 mg/kg, or you can make it a dealer’s choice. What are you going to do?

Robert H. I. Andtbacka, MD, CM: Well, I think we’ll still use ipilimumab at 10 mg/kg at this point in time, because we have more data for that, and we also have overall survival data for that. For 3 mg/kg, we don’t have the overall survival data yet. And I think with that, this was still very early in the presentation for these patients. The one thing I want to say that is really sort of a caution for me is that, in the 3 mg/kg dose, there were 2 patients who died because of that adjuvant therapy. I think that’s always a concern for us: these patients do not have any evidence of disease, yet there are 2 patients who are dying with that adjuvant therapy. In the 10 mg/kg setting, there were actually 8 patients who died because of the therapy itself. That, to me, is very concerning. So, 1.6% of patients who were getting 10 mg/kg died because of adjuvant treatment.

The other thing that is a bit perplexing to me is that if you look at the EORTC study that you discussed—specifically, the 10 mg/kg versus the placebo—the median progression-free survival was 27 months. Yet, in this trial right now, it is actually 3.9 years, which is about 45 months—so much longer. So, one thing I’d like to also understand is, what’s the difference between the patients here? If we look at the EORTC study, actually, those patients were stage 3A patients and were allowed in if they had 1-mm-sized metastasis in the sentinel lymph node, whereas in the ECOG 1609 study, there were stage 3B, 3C, and 4M1 patients.

Jeffrey S. Weber, MD, PhD: Yes, it did include stage 4 patients, correct.

Robert H. I. Andtbacka, MD, CM: Yes, but those stage 4 patients were about 8% of the total patients. A very small number of patients in the ECOG 1609 that actually were stage 4, yet we see this vast difference in the recurrence-free survival between these 2 groups. My question is, is there a difference in surgery? Because for much of these recurrences that we see, it’s going to be a locoregional recurrence. Is there a difference in surgery that we see in the EORTC study and in the ECOG study? We don’t know that. But these are things where as we get more data, I think we need to really look into what gives a 17-month difference in recurrence-free survival in the same dose.

Jeffrey S. Weber, MD, PhD: There does appear, in most of the adjuvant trials, to not be a stage migration but an outcome migration in that everyone puts together a trial at a certain point in time with expectations as to rate of relapse and survival. It’s always better than you expect, it seems, consistently.

Robert H. I. Andtbacka, MD, CM: I think we also have to question that then, and this is recurrence-free survival. Overall survival I would understand, but this is recurrence-free survival. So, what made that large difference in recurrence-free survival? I think there are data points as we go through this that we need to find out more about. With that, to answer your question directly, I think that as we design the next study, I would still use 10 mg/kg because we have more data on that at this point in time.

Transcript Edited for Clarity

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Transcript:

Jeffrey S. Weber, MD, PhD:
Jason, who do you decide to treat on drugs like adjuvant ipilimumab, which has been approved in the United States for over a year at 10 mg/kg, which is a significant dose—who do you decide to treat with that?

Jason J. Luke, MD: It’s obviously a difficult conversation. When we look at the data set from the EORTC 18071 study, the study included all stage 3 disease population, and that is the approved group of patients who could get ipilimumab. Now, in clinical practice, I find it’s a much more fraught conversation. I would say that I absolutely treat patients with ipilimumab if I have that sense from clinic that they have a high likelihood of recurrence, and that can be informed by several factors. But the point I will make is that, coming on after the discussion around completion lymph node dissection, there’s a substantial population of patients with low volume, single-node metastasis—those are absolutely the patients I would not treat with ipilimumab, where I think the likelihood of recurrence is actually quite low, and therefore the toxicity profile of giving the drug in the adjuvant setting is not justified.

Jeffrey S. Weber, MD, PhD: Although, interestingly, you could think about it the other way. You could think, “Well, we’re not doing the completion lymphadenectomy. I’m putting them at a little more risk of locoregional recurrence”—which I suspect we’ll find in MSLT-2—“maybe those are the people I should treat with adjuvant therapy.”

Jason J. Luke, MD: But if you look into the forest plots in the study, the actual benefit in terms of survival was relatively modest, if not nil, in the stage 3A population.

Georgina Long, MD, PhD: Jason, you’re not talking about the trial that was presented today, but you’re talking about the placebo versus 10 mg/kg study, which showed a hazard ratio of 0.72. That’s actually a nearly 30% risk reduction in death, which is an absolute benefit of 10%.

Jason J. Luke, MD: That was in the all-stage-3 population, though. And, if you look at the substages that drove most of that benefit, very little of it was from stage 3A.

Michael A. Davies, MD, PhD: One of the caveats to that trial, though, when I look at it, is the fact that in the patients who were on the placebo arm and recurred, it was actually a very small percentage of them who actually went on to receive ipilimumab for stage 4 disease, which we know can also have a survival benefit. So, I think there is some challenge to interpreting the results of that study.

Georgina Long, MD, PhD: In Australia, we don’t have ipilimumab 10 mg reimbursed, but even if we did, one of the things that we discuss with patients who are considering ipilimumab is, “Well, we don’t actually know whether or not waiting until you have stage 4 disease and treating with our best upfront Rolls Royce treatment is better for you,” because that trial was conducted around 2008, when we had no therapies available.

Jeffrey S. Weber, MD, PhD: True, but that’s a tough discussion, I must say. Let’s digress for a second. We heard a terrific talk today from Ahmad Tarhini from the University of Pittsburgh about early data from the ECOG-ACRIN 1609 study, which was a randomized, very large cooperative group study for patients with resected high-risk melanoma. It gave ipilimumab at a 3 mg/kg dose, ipilimumab at a 10 mg/kg dose, or high-dose interferon. It’s a study that has had at least 3 years of follow-up in almost all patients. Jason, what am I supposed to tell my patients based on those data? Could I safely tell patients, “Oh, no, you shouldn’t get 10 mg/kg, you should get 3 mg/kg.” What do you tell your patients?

Jason J. Luke, MD: Well, I haven’t told any of them yet, but what I plan to discuss with them is that it’s quite clear that the toxicity is increased with the higher dose—but that has been known. I actually have to say that I feel like we still need to take a bit of a cautious approach to these data. I think we all want to rush to the conclusion that they’re equivalent, and therefore, we can reduce the toxicity for patients. But there is also a study in the metastatic setting that shows there’s an increased survival advantage to giving the higher dose. So, in thinking about these data so far, I still haven’t been convinced that I would not treat patients in the adjuvant setting with 10 mg/kg, and I think that that does remain the standard of care until we really, truly see the readouts from that study with longer-term follow-up.

Georgina Long, MD, PhD: I couldn’t agree more, particularly when you look at the stage 4 patients in the trial and you see that the progression-free survival in the 3 mg/kg versus 10 mg/kg setting—this is for metastatic disease—shows no difference, yet we see a 10% overall survival benefit. So, here, we’ve just seen early data on the relapse-free survival. And we know for stage 3 melanoma that sometimes you don’t start to see separation in survival curves for 2 or 3 years, which is one of the problems with the DeCOG completion lymph node dissection trial.

Jeffrey S. Weber, MD, PhD: It sounds like there’s a little controversy. Let’s hear from Mike, and then let’s hear from Robert. Would you offer your patients 3 mg/kg based on the virtually identical 3-year relapse-free survival rates in that ECOG 1609 study? Or are you going to go with the standard, well-tested, 10 mg/kg treatment with a 40% rate of grade 3/4 immune-related adverse events?

Michael A. Davies, MD, PhD: I think, actually, we usually choose door C. At this point, for our patients in the adjuvant setting, we are really trying to get them onto clinical trials. I think that we’ve seen a complete revolution in the way we treat patients with stage 4 disease over the last 5 to 7 years. I anticipate that we’re similarly going to revolutionize adjuvant therapy. Really, what we try to do as often as possible is find clinical trials for patients to go on. In terms of directly answering your question, if you only have doors A and B, I agree at this point—I don’t think we’re ready to change the recommendation for adjuvant treatment to the 3 mg/kg dose, but I do think it was quite striking how overlapping the relapse-free survival curves were at this initial point in time. So, certainly, we’ll need close follow-up in terms of what the maturing results from the study are.

Jeffrey S. Weber, MD, PhD: The final aspect of this question is, Robert, you have to make the decision. You’re the PI of the next adjuvant trial of regimen X versus regimen Y versus ipilimumab, which is the standard of care. You can choose ipilimumab at 10 mg/kg or ipilimumab at 3 mg/kg, or you can make it a dealer’s choice. What are you going to do?

Robert H. I. Andtbacka, MD, CM: Well, I think we’ll still use ipilimumab at 10 mg/kg at this point in time, because we have more data for that, and we also have overall survival data for that. For 3 mg/kg, we don’t have the overall survival data yet. And I think with that, this was still very early in the presentation for these patients. The one thing I want to say that is really sort of a caution for me is that, in the 3 mg/kg dose, there were 2 patients who died because of that adjuvant therapy. I think that’s always a concern for us: these patients do not have any evidence of disease, yet there are 2 patients who are dying with that adjuvant therapy. In the 10 mg/kg setting, there were actually 8 patients who died because of the therapy itself. That, to me, is very concerning. So, 1.6% of patients who were getting 10 mg/kg died because of adjuvant treatment.

The other thing that is a bit perplexing to me is that if you look at the EORTC study that you discussed—specifically, the 10 mg/kg versus the placebo—the median progression-free survival was 27 months. Yet, in this trial right now, it is actually 3.9 years, which is about 45 months—so much longer. So, one thing I’d like to also understand is, what’s the difference between the patients here? If we look at the EORTC study, actually, those patients were stage 3A patients and were allowed in if they had 1-mm-sized metastasis in the sentinel lymph node, whereas in the ECOG 1609 study, there were stage 3B, 3C, and 4M1 patients.

Jeffrey S. Weber, MD, PhD: Yes, it did include stage 4 patients, correct.

Robert H. I. Andtbacka, MD, CM: Yes, but those stage 4 patients were about 8% of the total patients. A very small number of patients in the ECOG 1609 that actually were stage 4, yet we see this vast difference in the recurrence-free survival between these 2 groups. My question is, is there a difference in surgery? Because for much of these recurrences that we see, it’s going to be a locoregional recurrence. Is there a difference in surgery that we see in the EORTC study and in the ECOG study? We don’t know that. But these are things where as we get more data, I think we need to really look into what gives a 17-month difference in recurrence-free survival in the same dose.

Jeffrey S. Weber, MD, PhD: There does appear, in most of the adjuvant trials, to not be a stage migration but an outcome migration in that everyone puts together a trial at a certain point in time with expectations as to rate of relapse and survival. It’s always better than you expect, it seems, consistently.

Robert H. I. Andtbacka, MD, CM: I think we also have to question that then, and this is recurrence-free survival. Overall survival I would understand, but this is recurrence-free survival. So, what made that large difference in recurrence-free survival? I think there are data points as we go through this that we need to find out more about. With that, to answer your question directly, I think that as we design the next study, I would still use 10 mg/kg because we have more data on that at this point in time.

Transcript Edited for Clarity
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