Management of Relapsed/Refractory Metastatic Melanoma


Sanjiv S. Agarwala, MD: Perfect segue to talk about the resistant patients. Let’s start with the patient who has been on BRAF/MEK therapy and then they becomes resistant, now or later. Resistance, of course, is a very complicated issue. What is your approach to that patient? Obviously, you would continue immunotherapy, it’s a little easier. But what if the patient is BRAF wild-type, then it becomes a much better .....

Caroline Robert, MD, PhD: Usually you are very happy when you have a clinical trial and .... you can enroll your patients because otherwise you don’t have a lot of choices, and you’re back to chemotherapy sometimes. Usually the patients say, oh, chemotherapy doesn’t work, I don’t want it.

Sanjiv S. Agarwala, MD: Everyone has anecdotes, right, of chemotherapy working very well after, in 1 or 2 patients after immunotherapy.

Caroline Robert, MD, PhD: Yes.

Dirk Schadendorf, MD, PhD: I mean it depends if you have given nivolumab or ipilimumab. I mean, you are always, it’s much harder to find an alternative if you have given a PD-1 monotherapy, you are able either to go for the combination or for ipilimumab monotherapy, trying to give it with ipilimumab.

Sanjiv S. Agarwala, MD: So, what do you do, do you go to combo for that patient or do you switch to ipilimumab alone? What is your current practice?

Dirk Schadendorf, MD, PhD: It depends a little bit on the patient characteristics, how old, how much tumor, how aggressive the tumor is, and how much benefit the first treatment I gave. If the patient had a good tumor control let’s say for 2 years already, then the likelihood that we would go back to monotherapy is high. If there is a quick high tumor kinetics, we would be more aggressive and go to the combination.

Caroline Robert, MD, PhD: We are lacking data. We don’t have really controlled data.

Dirk Schadendorf, MD, PhD: Absolutely.

Caroline Robert, MD, PhD: And it’s too bad, because we don’t know. But the uncontrolled studies that have been presented are at least, tend to say that with the combination of nivolumab/ ipilimumab, we have more responses than with ipilimumab single agent following anti—PD-1.

Sanjiv S. Agarwala, MD: Next, if I were to ask you what is the biggest unmet need for melanoma today, what would you say that is in terms of the metastatic population? Obviously, second-line therapy comes to mind. For a BRAF wild-type patient after immunotherapy, what is the biggest unmet need?

Alexander Eggermont, MD, PhD: Well, the biggest unmet need is to deal with the most immunosuppressive population that is also present in metastatic melanoma. And it’s the M2 macrophage population. I’m personally convinced that this will be, probably, perhaps, the next breakthrough in immunotherapy combo. It’s like the third thing we need to do and is to knock out the M2 macrophages or revert them into M1 macrophage. So, you have these macrophage repolarizing agents like CCR5 inhibitor, you have CCR2/5.

Sanjiv S. Agarwala, MD: This is for refractory or up front? You’re talking about both?

Alexander Eggermont, MD, PhD: No, I would add it in a combination.

Sanjiv S. Agarwala, MD: Up front, yeah.

Alexander Eggermont, MD, PhD: To deepen responses and to break tolerance at yet another, not definitive level but perhaps at such a significant additional level.

Sanjiv S. Agarwala, MD: To improve the...

Alexander Eggermont, MD, PhD: That you would increase cure rates.

Sanjiv S. Agarwala, MD: Yeah, in frontline.

Alexander Eggermont, MD, PhD: That will show up, that the 5-year survival rates for advanced melanoma, that already with the anti—PD-1/anti–CTLA-4 combo will be above 50% at 5 years, will go up to 70%. And then melanoma is the new Hodgkin lymphoma. And that’s what we should be achieving, and I see no reason why we should not be achieving that.

Sanjiv S. Agarwala, MD: Well, if the unmet need is something that could go on, and on, and on.

Caroline Robert, MD, PhD: Well, we still have the patients arriving with LDH, high tumor burden.

Sanjiv S. Agarwala, MD: Yeah, we didn’t talk about that too much.

Caroline Robert, MD, PhD: For them.

Sanjiv S. Agarwala, MD: It’s still a very tough problem.

Caroline Robert, MD, PhD: It’s still melanoma, I mean it’s .....

Dirk Schadendorf, MD, PhD: I think that the main challenge is that we still treat the patient, that we don’t have already at first-line. I mean, it’s getting even more complicated.

Sanjiv S. Agarwala, MD: It’s patient selection.

Dirk Schadendorf, MD, PhD: Yes. We don’t have really good selection markers and will be getting more complicated with adjuvant therapy over the next five years since stage II will have, and that will be the challenge.

Sanjiv S. Agarwala, MD: Well, you know, this has been very interesting and we’re running out of time. So, I want to thank you all for your contributions on the discussion. And, on behalf of our panel, we thank you for joining us. Hope you found this Peer Exchange discussion to be useful and informative and look forward to new and exciting data coming out at future meetings. Thank you very much.

Transcript Edited for Clarity

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