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Metastatic Melanoma: Key Trial Updates

Panelists: Sanjiv S. Agarwala, MD, Temple University School of Medicine; Alexander Eggermont, MD, PhD, Institut Gustave Roussy; Caroline Robert, MD, PhD, Institut Gustave Roussy; Dirk Schadendorf, MD, PhD, West German Cancer Center at University Hospital Essen
Published: Wednesday, Aug 07, 2019



Transcript: 

Sanjiv S. Agarwala, MD: Dirk, talking about the BRAF-positive population, the COLUMBUS trial was updated, you know, with the most recent BRAF/MEK combo. And Alex’s points are very interesting. That data were looking more impressive. Were you impressed with that? Is there something in that combination that’s different? What are your thoughts on that update?

Dirk Schadendorf, MD, PhD: I think the clinical efficacy data for encorafenib and binimetinib are very well in line with the other BRAF/MEK combinations. Third in market, I think there is absolutely no doubt that this combination is working. It’s clinically efficient and is working as good as what we have in hand. I think the main discriminator is obviously the toxicity profile. We have distinct toxicity profile for vemurafenib-cobimetinib, and we have a distinct toxicity profile for dabrafenib-trametinib with pyrexia. And I think for that I think one has to consider encorafenib-binimetinib as an alternative, either in frontline or in certain circumstances where you are not willing to accept toxicities anymore, where you expect in front certain toxicities. I think even in certain offices, there might be a change in practice based on the toxicity profile. But I mean, that’s probably an individual decision of investigators and tailored to the patient.

Sanjiv S. Agarwala, MD: And that’s the best discriminator.

Caroline Robert, MD, PhD: I think it’s very good news that we can have the choice, because from 1 patient to another, it’s different.

Sanjiv S. Agarwala, MD: Do you switch if you have a patient on, say, 1 combination and they have some unique toxicity? Then do you switch to another 1?

Caroline Robert, MD, PhD: Yes, it can happen, so it’s good that you can do that.

Sanjiv S. Agarwala, MD: You do that, right? There are good choices, yeah.

Alexander Eggermont, MD, PhD: The photosensitivity, for instance.

Caroline Robert, MD, PhD: Photosensitivity for vemurafenib, the fever and the chills for dabrafenib…

Dirk Schadendorf, MD, PhD: It’s not only that. I mean, there are also some other soft decision-making points like number of pills, whether you need association to food or not. There are several factors which might, in certain patients, be relevant.

Caroline Robert, MD, PhD: Yeah. Keep that for…

Sanjiv S. Agarwala, MD: Alex, you mentioned earlier a couple of times about low-dose ipilimumab. So I want to turn now to alternative schedules of combination therapy. And we’ve had some data that have been coming out. Maybe I’ll start with you, Dirk, in terms of the standard-dose pembrolizumab, alternate ipilimumab, KEYNOTE-029, that cohort 1c that keeps popping up. And we had an update. What are your thoughts on that? It’s looking interesting to me that we seem to be having similar efficacy and lower toxicity. But please, what are your thoughts on that?

Dirk Schadendorf, MD, PhD: We have a comparative trial, CheckMate 511.

Sanjiv S. Agarwala, MD: I want to talk about that too. Go ahead and talk about both, yeah.

Dirk Schadendorf, MD, PhD: There we have a head-to-head comparison looking, actually, with an endpoint, toxicity, and there’s clear evidence that the lower dose of ipilimumab is producing a lower dose of toxicity, which is cutting the toxicity percentage-wise by 50%. The question is, is this change by efficacy? Is there any change by lowering inflammatory stimulus by ipilimumab.

Sanjiv S. Agarwala, MD: Especially with long-term survival, which is a big issue, right?

Dirk Schadendorf, MD, PhD: Yes. So obviously that’s hard to answer. In my view, the KEYNOTE-029 is also not adding to that too much because that’s a trial that is not comparing with a standard dose. It’s a select patient population. I think it reemphasized that there is certain activity, and the toxicity is much easier to manage.

Caroline Robert, MD, PhD: But we cannot be sure that it has the same efficacy as ipilimumab 3 mg.

Dirk Schadendorf, MD, PhD: We stick to that.

Sanjiv S. Agarwala, MD: Is anyone here using 1 mg of ipilimumab outside clinical trial right now?

Caroline Robert, MD, PhD: Outside clinical trials, no.

Sanjiv S. Agarwala, MD: Alex, are you?

Alexander Eggermont, MD, PhD: No, but I would be very happy to. If I were in private practice, that’s what I would be using all the time.

Sanjiv S. Agarwala, MD: To be honest.

Alexander Eggermont, MD, PhD: And if I would be living in a country where they have ipilimumab, then I would be using it all the time.

Dirk Schadendorf, MD, PhD: On the other hand, the questions we’re always talking about: making a cold tumor hot. And for that, most of the time we need inflammation…and I think ipilimumab is a prototype of a molecule producing inflammation. Maybe we have other ways to produce inflammation which are more efficient or less toxic. I don’t know. I think we need to work on that. But I think inflammation is a critical factor in priming, in all the immunological function. This inflammation by itself is going along with toxicity. I mean, we have done that with high-dose IL-2, and even with high-dose interferon we have done the same thing. We have produced inflammation.

Alexander Eggermont, MD, PhD: Yeah, I know, but in the melanoma field, anti–PD-1 is such an overachiever that it may be different in the melanoma field, and just 1 mg of ipilimumab may be just sufficient in the combination.

Dirk Schadendorf, MD, PhD: Maybe, maybe.

Alexander Eggermont, MD, PhD: Because that’s what the neoadjuvant data thus far seem to indicate as well. There is additional evidence that supports the idea that in melanoma, 1 mg of ipilimumab might be just fine with anti–PD-1. Whether that’s going to be the same thing for MSI [microsatellite instability] tumors, for other tumors that are more difficult to treat, or for lung cancer, we don’t really know. There are some indications that they may prefer 3 mg of ipilimumab.

Sanjiv S. Agarwala, MD: Is it fair to say that we need more data? We need longer follow-up and hopefully more randomized data, right? Anyway, that’s interesting. I think it’s really a good way to—as Dirk, you tried to show in CheckMate-067—improve quality of life.

Transcript Edited for Clarity

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Transcript: 

Sanjiv S. Agarwala, MD: Dirk, talking about the BRAF-positive population, the COLUMBUS trial was updated, you know, with the most recent BRAF/MEK combo. And Alex’s points are very interesting. That data were looking more impressive. Were you impressed with that? Is there something in that combination that’s different? What are your thoughts on that update?

Dirk Schadendorf, MD, PhD: I think the clinical efficacy data for encorafenib and binimetinib are very well in line with the other BRAF/MEK combinations. Third in market, I think there is absolutely no doubt that this combination is working. It’s clinically efficient and is working as good as what we have in hand. I think the main discriminator is obviously the toxicity profile. We have distinct toxicity profile for vemurafenib-cobimetinib, and we have a distinct toxicity profile for dabrafenib-trametinib with pyrexia. And I think for that I think one has to consider encorafenib-binimetinib as an alternative, either in frontline or in certain circumstances where you are not willing to accept toxicities anymore, where you expect in front certain toxicities. I think even in certain offices, there might be a change in practice based on the toxicity profile. But I mean, that’s probably an individual decision of investigators and tailored to the patient.

Sanjiv S. Agarwala, MD: And that’s the best discriminator.

Caroline Robert, MD, PhD: I think it’s very good news that we can have the choice, because from 1 patient to another, it’s different.

Sanjiv S. Agarwala, MD: Do you switch if you have a patient on, say, 1 combination and they have some unique toxicity? Then do you switch to another 1?

Caroline Robert, MD, PhD: Yes, it can happen, so it’s good that you can do that.

Sanjiv S. Agarwala, MD: You do that, right? There are good choices, yeah.

Alexander Eggermont, MD, PhD: The photosensitivity, for instance.

Caroline Robert, MD, PhD: Photosensitivity for vemurafenib, the fever and the chills for dabrafenib…

Dirk Schadendorf, MD, PhD: It’s not only that. I mean, there are also some other soft decision-making points like number of pills, whether you need association to food or not. There are several factors which might, in certain patients, be relevant.

Caroline Robert, MD, PhD: Yeah. Keep that for…

Sanjiv S. Agarwala, MD: Alex, you mentioned earlier a couple of times about low-dose ipilimumab. So I want to turn now to alternative schedules of combination therapy. And we’ve had some data that have been coming out. Maybe I’ll start with you, Dirk, in terms of the standard-dose pembrolizumab, alternate ipilimumab, KEYNOTE-029, that cohort 1c that keeps popping up. And we had an update. What are your thoughts on that? It’s looking interesting to me that we seem to be having similar efficacy and lower toxicity. But please, what are your thoughts on that?

Dirk Schadendorf, MD, PhD: We have a comparative trial, CheckMate 511.

Sanjiv S. Agarwala, MD: I want to talk about that too. Go ahead and talk about both, yeah.

Dirk Schadendorf, MD, PhD: There we have a head-to-head comparison looking, actually, with an endpoint, toxicity, and there’s clear evidence that the lower dose of ipilimumab is producing a lower dose of toxicity, which is cutting the toxicity percentage-wise by 50%. The question is, is this change by efficacy? Is there any change by lowering inflammatory stimulus by ipilimumab.

Sanjiv S. Agarwala, MD: Especially with long-term survival, which is a big issue, right?

Dirk Schadendorf, MD, PhD: Yes. So obviously that’s hard to answer. In my view, the KEYNOTE-029 is also not adding to that too much because that’s a trial that is not comparing with a standard dose. It’s a select patient population. I think it reemphasized that there is certain activity, and the toxicity is much easier to manage.

Caroline Robert, MD, PhD: But we cannot be sure that it has the same efficacy as ipilimumab 3 mg.

Dirk Schadendorf, MD, PhD: We stick to that.

Sanjiv S. Agarwala, MD: Is anyone here using 1 mg of ipilimumab outside clinical trial right now?

Caroline Robert, MD, PhD: Outside clinical trials, no.

Sanjiv S. Agarwala, MD: Alex, are you?

Alexander Eggermont, MD, PhD: No, but I would be very happy to. If I were in private practice, that’s what I would be using all the time.

Sanjiv S. Agarwala, MD: To be honest.

Alexander Eggermont, MD, PhD: And if I would be living in a country where they have ipilimumab, then I would be using it all the time.

Dirk Schadendorf, MD, PhD: On the other hand, the questions we’re always talking about: making a cold tumor hot. And for that, most of the time we need inflammation…and I think ipilimumab is a prototype of a molecule producing inflammation. Maybe we have other ways to produce inflammation which are more efficient or less toxic. I don’t know. I think we need to work on that. But I think inflammation is a critical factor in priming, in all the immunological function. This inflammation by itself is going along with toxicity. I mean, we have done that with high-dose IL-2, and even with high-dose interferon we have done the same thing. We have produced inflammation.

Alexander Eggermont, MD, PhD: Yeah, I know, but in the melanoma field, anti–PD-1 is such an overachiever that it may be different in the melanoma field, and just 1 mg of ipilimumab may be just sufficient in the combination.

Dirk Schadendorf, MD, PhD: Maybe, maybe.

Alexander Eggermont, MD, PhD: Because that’s what the neoadjuvant data thus far seem to indicate as well. There is additional evidence that supports the idea that in melanoma, 1 mg of ipilimumab might be just fine with anti–PD-1. Whether that’s going to be the same thing for MSI [microsatellite instability] tumors, for other tumors that are more difficult to treat, or for lung cancer, we don’t really know. There are some indications that they may prefer 3 mg of ipilimumab.

Sanjiv S. Agarwala, MD: Is it fair to say that we need more data? We need longer follow-up and hopefully more randomized data, right? Anyway, that’s interesting. I think it’s really a good way to—as Dirk, you tried to show in CheckMate-067—improve quality of life.

Transcript Edited for Clarity
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