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Neoadjuvant Therapy for Melanoma

Panelists: Jeffrey Weber, MD, PhD, NYU Langone Medical Center; Reinhard Dummer, MD, University of Zurich Hospital;Axel Hauschild, MD, University of Kiel;Caroline Robert, MD, PhD, Gustave Roussy; Dirk Schadendorf, MD, University Hospital Essen
Published: Wednesday, Dec 14, 2016


Transcript:

Jeffrey Weber, MD, PhD:
Dirk, what about neoadjuvant therapy? We actually, for the first time, heard about a neoadjuvant trial here at ESMO; this was Christian Blank’s study. So, is there a place for neoadjuvant therapy in patients with sort of the bulky high-risk stage IIIc disease, and now we call it stage IIId disease?

Dirk Schadendorf, MD: Yes. I think Caroline already described the challenge for the future in the stage 3III and stage IV disease areas. We have to wait for a long time to see really that the treatment we are giving in our clinical trials are effective. So, 5 years ago, within 1 year we would receive the clinical results on response rate, PFS, and overall survival, and the study was over. Now, we are looking, and are not satisfied, if we see one-year overall survival rates. The times are also over, that we have after one year, a 30% difference in one-year survival rates as we have seen, for example, for PD-1 antibodies and in comparison to ipilimumab or DTIC. So, I think the differences will be smaller and probably we have to wait for longer times. This opens the space for neoadjuvant treatment because I think neoadjuvant trials will give us earlier insight on response rate, sensitivity of the disease, and also, possibly, on ways to combine or sequence treatments that we have available, which might then be tested in larger trials.

Jeffrey Weber, MD, PhD: Okay. But, I was struck by the almost complete assumption that somehow neoadjuvant therapy would be superior to adjuvant therapy. Reinhard, do you buy into this?

Reinhard Dummer, MD: Many people argue this, but, I think, we have to be very careful. The principle of neoadjuvant therapy was never systematically studied, so we have these nice studies that show us a perfect response rate, but if we look for Caroline’s data for dabrafenib/trametinib, patients with low LDH and limited tumor burden do better, even those with lymph node metastases who can respond very nicely. So, this doesn’t prove anything. If you want to prove the principle, you have to take the same treatment and split it up into two parts—neoadjuvant part and then adjuvant part—and compare it directly to the conventional treatment. I don’t see a study around that will ever investigate this at the moment. So, the principle of neoadjuvant is not established. On the other hand, certainly it’s very attractive, and it gives us early information and the big advantage is it gives us tissue for extensive translational research. Maybe these translational data will help us to decide which combination or which treatment approach is more powerful.

Jeffrey Weber, MD, PhD: So, a good research tool, but maybe not so ready for prime time.

Reinhard Dummer, MD: Exactly.

Jeffrey Weber, MD, PhD: Just to cap it off, Axel, the Christian Blank study, what did you conclude from that?

Axel Hauschild, MD: I may ask a very provocative question. Aren’t we using neoadjuvant approaches every day with our melanoma patients?

Caroline Robert, MD, PhD: Exactly, that’s what I think.

Axel Hauschild, MD: It could be the idea to shrink the tumor, to shrink the metastases in order to make them operable one day and resect something, and do radiation on top of it—just to do everything to achieve a complete response and no evidence of disease in these patients. But, we’re not calling it neoadjuvant because neoadjuvant is something which you need to plan prospectively. Reinhard is correct, there are very few studies on neoadjuvant treatment. I believe these are always more or less pilot studies to achieve data on biomarkers. That’s my idea behind neoadjuvant trials. The data are good for nivolumab plus ipilimumab, but it was presented at a very early time point, so there is no long follow-up. So, they are simply immature data.

Jeffrey Weber, MD, PhD: Okay. Were you surprised at the results of the Christian Blank study? I mean that many patients couldn’t go beyond their first induction cycle?

Caroline Robert, MD, PhD: No, it’s so not surprising. I think we are misled by our classification. Because we say neoadjuvant in patients with a big tumor load. But, these patients we know are probably already metastatic, as well. So, in fact, then, we treat them as if they were locally advanced because in our head they are stage IIIc. But, in fact, I think it’s more the question of duration of treatment in metastatic disease that is less advanced in fact.

Jeffrey Weber, MD, PhD: Yes.

Caroline Robert, MD, PhD: Now, I realize that maybe the question is, if we give a new adjuvant treatment, okay, we shrink the tumor because we have drugs that are effective for that. And, then, after we give the treatment, for some time, depending on the protocols, but finally we probably treat them in this way. Some patients were in the early stage of the metastatic disease. So, finally, how long do we need to treat these patients?

Jeffrey Weber, MD, PhD: Okay, so actually since we’re talking about metastatic disease, it’s a good segue to our thoughts on metastatic disease.

Transcript Edited for Clarity
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Transcript:

Jeffrey Weber, MD, PhD:
Dirk, what about neoadjuvant therapy? We actually, for the first time, heard about a neoadjuvant trial here at ESMO; this was Christian Blank’s study. So, is there a place for neoadjuvant therapy in patients with sort of the bulky high-risk stage IIIc disease, and now we call it stage IIId disease?

Dirk Schadendorf, MD: Yes. I think Caroline already described the challenge for the future in the stage 3III and stage IV disease areas. We have to wait for a long time to see really that the treatment we are giving in our clinical trials are effective. So, 5 years ago, within 1 year we would receive the clinical results on response rate, PFS, and overall survival, and the study was over. Now, we are looking, and are not satisfied, if we see one-year overall survival rates. The times are also over, that we have after one year, a 30% difference in one-year survival rates as we have seen, for example, for PD-1 antibodies and in comparison to ipilimumab or DTIC. So, I think the differences will be smaller and probably we have to wait for longer times. This opens the space for neoadjuvant treatment because I think neoadjuvant trials will give us earlier insight on response rate, sensitivity of the disease, and also, possibly, on ways to combine or sequence treatments that we have available, which might then be tested in larger trials.

Jeffrey Weber, MD, PhD: Okay. But, I was struck by the almost complete assumption that somehow neoadjuvant therapy would be superior to adjuvant therapy. Reinhard, do you buy into this?

Reinhard Dummer, MD: Many people argue this, but, I think, we have to be very careful. The principle of neoadjuvant therapy was never systematically studied, so we have these nice studies that show us a perfect response rate, but if we look for Caroline’s data for dabrafenib/trametinib, patients with low LDH and limited tumor burden do better, even those with lymph node metastases who can respond very nicely. So, this doesn’t prove anything. If you want to prove the principle, you have to take the same treatment and split it up into two parts—neoadjuvant part and then adjuvant part—and compare it directly to the conventional treatment. I don’t see a study around that will ever investigate this at the moment. So, the principle of neoadjuvant is not established. On the other hand, certainly it’s very attractive, and it gives us early information and the big advantage is it gives us tissue for extensive translational research. Maybe these translational data will help us to decide which combination or which treatment approach is more powerful.

Jeffrey Weber, MD, PhD: So, a good research tool, but maybe not so ready for prime time.

Reinhard Dummer, MD: Exactly.

Jeffrey Weber, MD, PhD: Just to cap it off, Axel, the Christian Blank study, what did you conclude from that?

Axel Hauschild, MD: I may ask a very provocative question. Aren’t we using neoadjuvant approaches every day with our melanoma patients?

Caroline Robert, MD, PhD: Exactly, that’s what I think.

Axel Hauschild, MD: It could be the idea to shrink the tumor, to shrink the metastases in order to make them operable one day and resect something, and do radiation on top of it—just to do everything to achieve a complete response and no evidence of disease in these patients. But, we’re not calling it neoadjuvant because neoadjuvant is something which you need to plan prospectively. Reinhard is correct, there are very few studies on neoadjuvant treatment. I believe these are always more or less pilot studies to achieve data on biomarkers. That’s my idea behind neoadjuvant trials. The data are good for nivolumab plus ipilimumab, but it was presented at a very early time point, so there is no long follow-up. So, they are simply immature data.

Jeffrey Weber, MD, PhD: Okay. Were you surprised at the results of the Christian Blank study? I mean that many patients couldn’t go beyond their first induction cycle?

Caroline Robert, MD, PhD: No, it’s so not surprising. I think we are misled by our classification. Because we say neoadjuvant in patients with a big tumor load. But, these patients we know are probably already metastatic, as well. So, in fact, then, we treat them as if they were locally advanced because in our head they are stage IIIc. But, in fact, I think it’s more the question of duration of treatment in metastatic disease that is less advanced in fact.

Jeffrey Weber, MD, PhD: Yes.

Caroline Robert, MD, PhD: Now, I realize that maybe the question is, if we give a new adjuvant treatment, okay, we shrink the tumor because we have drugs that are effective for that. And, then, after we give the treatment, for some time, depending on the protocols, but finally we probably treat them in this way. Some patients were in the early stage of the metastatic disease. So, finally, how long do we need to treat these patients?

Jeffrey Weber, MD, PhD: Okay, so actually since we’re talking about metastatic disease, it’s a good segue to our thoughts on metastatic disease.

Transcript Edited for Clarity
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