Single vs Dual Checkpoint Inhibition in Melanoma

Transcript:Jeffrey Weber, MD, PhD: If you want to talk about controversies, how about the urban legend number 3 that everybody needs combination immunotherapy versus patients really only need a single PD-1 inhibitor? How do you make that decision?

Axel Hauschild, MD: That’s a good question for my friend, Dirk. I’m responding to it. I think nobody knows how we could distinguish for the indication of PD-1 antibodies and PD-1 plus—in this case, it’s nivolumab plus ipilimumab, because it’s the only approved combination. And it’s a big question right now, not only in Germany. We have rewritten our guidelines. They were released in June 2016, so it’s very fresh.

And the scheme has become simpler because we believe in Germany—and this was an interdisciplinary board discussing the guidelines—that there are no data available telling us at this point in time if we need to go ahead with ipilimumab plus nivolumab for all patients or just the PD-1 antibody. Or, for patients who are carrying a BRAF mutation, the PD-1 plus a MEK inhibitor. They are all on the same line, in first-line, so it’s a decision that needs to be made on individual criteria. And trust me, I think we haven’t identified very good individual criteria right now. So, it’s very much a gut feeling in each board. And it’s also a matter of believing in something or not believing in something. But, certainly for ipilimumab and nivolumab, the toxicities are also driving decisions.

If somebody has clear contraindications for this, and you discuss toxicities, and the patient is saying, “By no means do I want to accept this magnitude of toxicities,” you can go ahead with PD-1. The most burning question for me is, if you start with single agent PD-1 antibody, if in second-line when patients have a progressive disease, whether they will have a benefit with ipilimumab plus nivolumab.

Jeffrey Weber, MD, PhD: And there is a trial that will test that question.

Axel Hauschild, MD: Yes, but no data will ever get there. I have not even seen a case report on it.

Caroline Robert, MD, PhD: No, it needs to be evaluated in a trial.

Jeffrey Weber, MD, PhD: Have you ever done that? In fact, has anyone at the table ever taken a patient who had PD-1 inhibitor alone, progressed, and then given them ipilimumab plus nivolumab and seen a significant response?

Dirk Schadendorf, MD: No.

Jeffrey Weber, MD, PhD: Never tried it or …?

Dirk Schadendorf, MD: No, I have not seen a response. So, what we have done is we have added ipilimumab, let’s say at the second cycle very early on, because we believed that there was some increase in LDH where monotherapy would not work enough—in a true progressive patient—and then switched to the combination.

Jeffrey Weber, MD, PhD: So, you’ve tried it, but it’s not worked. How about you?

Caroline Robert, MD, PhD: No, I have not done that because the combination is not reimbursed yet. We have it with clinical trials, and most of the clinical trials would exclude patients who have received a PD-1 inhibitor.

Jeffrey Weber, MD, PhD: Of course, yes.

Caroline Robert, MD, PhD: But I have given ipilimumab after all, and sometimes it’s worked.

Jeffrey Weber, MD, PhD: Of course.

Axel Hauschild, MD: In 10%, yes.

Jeffrey Weber, MD, PhD: We agree. But, Reinhard, have you ever given ipilimumab/nivolumab to someone who failed a PD-1 antibody?

Reinhard Dummer, MD: I have done this several times, and especially in the setting that we started with anti-PD-1 monotherapy therapy—these are BRAF-mutated—they go on to targeted therapy, and then they go into this smoldering, progressive disease. And at this time point, you know that the effect of targeted therapy will be limited, and you know that this patient will have not ever seen ipilimumab. So, then the question is, should you put this patient on ipilimumab monotherapy or whether the alternative is that you use combinations? And, actually, I’m encouraged by some data from Erlangen, and I have seen the manuscript. It’s only a case series, very few cases. And in this case series, there are a few responses. Therefore, we have made the decision very recently in a number of patients that we don’t use ipilimumab monotherapy, but the ipilimumab/nivolumab combination in this setting.

Jeffrey Weber, MD, PhD: You’re saying it’s a series of 10 patients who were treated with PD-1 blockade and then progressed and got ipilimumab/nivolumab?

Caroline Robert, MD, PhD: No. They got first the BRAF/MEK and then…

Jeffrey Weber, MD, PhD: So, they got BRAF/MEK.

Dirk Schadendorf, MD: Axel is the coauthor.

Axel Hauschild, MD: I’m the coauthor of this, so maybe I can tell you about this.

Jeffrey Weber, MD, PhD: Well, in that case, tell us all about it.

Axel Hauschild, MD: It was a study done by Lucie Heinzerling from Erlangen on 10 patients. All of the patients had progressive disease on ipilimumab. At this time, they could switch to PD-1 antibodies. They were not approved in Germany at this time, so that was the early access program where they need to be pretreated with ipilimumab. And then they failed on ipilimumab, they failed on the anti-PD-1. If this was pembrolizumab or nivolumab, it doesn’t matter. All of these 10 patients got low-dose ipilimumab, 1 mg/kg, and full-dose pembrolizumab, the scheme which has been described at ASCO this year. Ten patients, one partial response, and two stabilizations. All the other patients had progressive disease. The conclusion was it might not be very efficacious in this setting if you have a progressive disease on two drugs. But, for me, the most interesting observation is there was no CTC grade 3-4 toxicities. So, maybe….

Jeffrey Weber, MD, PhD: But, they got low-dose ipilimumab, yes?

Axel Hauschild, MD: No, no, no. Even there you have 37% grade 3-4 toxicity as described for full-dose pembrolizumab and low-dose ipilimumab. But here there was not a single case that was grade 3-4 toxicity. Maybe it’s burned out of all the organs, which had already been infiltrated by T lymphocytes because they were treated with ipilimumab. There was almost no toxicity.

Jeffrey Weber, MD, PhD: Okay, so in general practice when you’re using PD-1 inhibitors, do you tend to favor off-protocol pembrolizumab for the 3-week schedule or nivolumab? Is there a difference? Is it a patient convenience issue? I know what we do in the United States, but is it the same for you?

Axel Hauschild, MD: I don’t know how it is in the United States. But, in Germany, most of the centers are favoring the 3-week scheme over the 2-week scheme for practical reasons. It’s simply because it’s the patient convenience, but it’s also the convenience of the treating physicians. In dermatology units and dermato-oncology units, we have so many infusions to manage. And everybody is happy if we’re not doing it every 2 weeks, but we can do it every 3 weeks. But, still, I think the drugs are the same in terms of efficacy and tolerability. So, it’s a practical issue. There are testings of 2 weeks versus 4 weeks for nivolumab now underway. And certainly, one of the reasons is this practical issue, and also the flat-dose discussion. I heard it’s approved in the United States now for various cancers, including melanoma.

Jeffrey Weber, MD, PhD: Yes, the nivolumab flat dose is now approved.

Axel Hauschild, MD: Nivolumab at 240 mg as a flat dose. So, that’s something interesting that’s coming now, and I think the field is changing.

Jeffrey Weber, MD, PhD: Yes.

Caroline Robert, MD, PhD: Every what?

Jeffrey Weber, MD, PhD: The FDA has approved the use of a flat dose every 2 weeks with nivolumab at 240 mg, which makes sense because you waste less. In other words, you’ll use the whole vial at 240 mg, and there’s really not much of a dose response for nivolumab.

Caroline Robert, MD, PhD: But, it’s still every 2 weeks.

Jeffrey Weber, MD, PhD: Yes, it’s every 2 weeks. But, perhaps in the future, there’ll be an every-4-weeks regimen.

Axel Hauschild, MD: There’s a study: the 240 mg versus 480 mg. So, you give the same dose in a 4-week time period?

Jeffrey Weber, MD, PhD: Yes.

Axel Hauschild, MD: You give it twice a month versus once a month, and I think that’s an interesting study.

Jeffrey Weber, MD, PhD: And with a half-life, it turns out the PD-1 half lives are probably closer to 3 weeks than 2 weeks, so it would make sense to give it every 4.

Reinhard Dummer, MD: Yes, also an interesting development is nursing. There are nursing programs now where the nurses go home to the patient and apply anti-PD-1 therapy.

Caroline Robert, MD, PhD: Maybe not for the first infusion but…

Reinhard Dummer, MD: Not for the first time, but if you are on long-term therapy, I think this is also a strategy. I agree with Axel. Our outpatient clinics are packed.

Transcript Edited for Clarity