Advances in the Treatment of Malignant Melanoma - Episode 14

Targeted Therapy Versus IO for Relapsed/Refractory Melanoma

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Jason J. Luke, MD, FACP: Can I make a comment quickly to follow up on one thing that Adil mentioned about checkpoint blockade in the refractory disease setting? I want to highlight quickly, because we didn’t talk about it yet, the data for using ipilimumab in the second line, and adding it onto PD-1 because there were 2 big abstracts on that, that I don’t want to say are practice-changing, but I definitely think will influence people’s thought process. One was a second-line phase 2 study of adding low-dose ipilimumab after initial PD-1 failure. That study showed a 27% response rate in 70 patients. That was augmented by a retrospective study from the MIA [Melanoma Institute Australia], where they looked at the experience of giving ipilimumab/nivolumab after nivolumab or PD-1. They got a 32% response rate in a group of 180 patients. Those are 2 reasonably large data sets to suggest that you could get more activity by continuing PD-1 and adding ipilimumab than you would of just giving ipilimumab because the response rate we would expect for ipilimumab alone in that setting is about 13% to 15%. This looks to be almost double that.

It was mentioned before that you’re wringing all the T-cells out. I think that’s true to some extent, but in the immediate post–PD-1 monotherapy space, it’s looking more and more like giving that combination therapy may be better than giving ipilimumab monotherapy. There is more work to do there. There is a SWOG trial that’s specifically randomizing patients to look at that. I think that’s worth being cognizant of, because if patients are having rapid progression after PD-1 monotherapy and they’re BRAF wild type, I personally would recommend continuing the PD-1 and adding the ipilimumab on top of it. It is an open question. Now reasonable-sized data series support that.

Jeffrey S. Weber, MD, PhD: I think a lot of people do that as their routine standard if they’re not in a protocol setting. On the other hand, how often in your practice, or Adil, Ryan, or Su, do you give someone single-agent PD-1 blockade? How often do you do that versus giving them the combination?

Sunandana Chandra, MD: In my practice, I tend to be pretty aggressive. I do use a lot of combination immunotherapy. One thing that’s changed recently with the coronavirus disease 2019 pandemic, however, we felt, perhaps scaling back a little bit. The responses with anti–PD-1 alone are actually quite remarkable. To stave off some potential AEs [adverse events] that would put people at risk by bringing them into the hospital, etc, we have been using a little bit more anti–PD-1 alone. In general, I would say I use a lot of combination, and certainly for patients with brain metastases.

Jeffrey S. Weber, MD, PhD: Adil, is it the same for you?

Adil Daud, MD: I don’t want to pretend to be consistent on this issue because I have argued all kinds of sides of this. In this instant, listening to you guys talk, I feel like a lot of the time, I do use combination therapy up front, unless I can be almost positive from looking at the T cells, that somebody will have a response, or if somebody has very low-volume disease, or is older and doesn’t want to come in a lot, or is quite worried about toxicity. But I’ve been very easygoing in terms of stopping combination therapy after 2 or 3 cycles. Once somebody has a response, that heavy lifting with PD-1 blockade seems to be done pretty early, and what you’re getting a year or 2 years out probably isn’t a whole lot. I’m quick to stop combination therapy. So far, I’m sticking to the 3 mg of ipilimumab, but really there are data on either side.

Jeffrey S. Weber, MD, PhD: Jason, do you feel the same way?

Jason J. Luke, MD, FACP: I wouldn’t argue with anybody’s perspective. I tend to still be somebody who uses clinical factors for selecting patients for ipilimumab/nivolumab combination, which is high-risk disease, so high LDH [lactate dehydrogenase], liver, bone metastases, and brain metastases. In patients who don’t have those features, I tend to still defer toward PD-1 combinations in clinical trials. I tend to give monotherapy there. That’s why the data for bringing in ipilimumab in the second line, to me, was, I don’t want to say reassuring because every patient’s different and it’s hard to know, but it’s still possible to salvage some of the patients to get responses in the second line by adding the ipilimumab. I might be biased toward being less intensive up front unless there are clear clinical factors that really push me that way.

Jeffrey S. Weber, MD, PhD: I would agree that the Daniel Olson, MD, article from your former institution from Chicago. Then the Ines Pires da Silva, MD, PhD, which is Melanoma InstituteAustralia. Olson’s was prospective. I think it was something like 70 patients. Then da Silva was retrospective with 355. I would say those are important. For me, they’d be practice-affirming, as opposed to practice-changing. Ryan, are they practice-changing for you or affirming?

Ryan J. Sullivan, MD: No, I tend to agree more with Jason here. I don’t know if it’s a competition, but I probably give more single-agent PD-1 in the front line than most. My rationale is, it comes from when we worked together on the CheckMate 064 study, which randomized patients either starting with ipilimumab or nivolumab, and then they switched to nivolumab or ipilimumab. Then they went to maintenance nivolumab. The results of the trial were interesting. Obviously, starting with nivolumab was better.

What helped me understand the impact of these 2 drugs together was that when you gave ipilimumab soon after nivolumab, a lot of patients who weren’t having clinical benefit started to have clinical benefit. They all started to have toxicity, but that cemented into me that if there are patients for whom you can wait 3 months to see if PD-1 monotherapy is effective, you might as well, because you probably are salvaging most of the patients that you’re treating with combination up front who are going to get the benefit of ipilimumab. The da Silva and the Olson studies affirm, as you say, that bias that giving ipilimumab afterward is probably OK. More importantly, giving it with a continued PD-1 inhibitor is a reasonable way to go.

If you’re aged 60 or 70 or 80, or 20, it’s hard to argue with younger patients getting combination with survival benefit that may be better by that few percentage points. In older folks who have comorbidities, even if they’re not autoimmune comorbidities, getting a 30% or 40% chance of having durable remission with the PD-1 inhibitor, and if they don’t have that, you might be able to make up the durable remission rate with second-line ipilimumab/nivolumab. That’s a reasonable way to go for patients who don’t need a response right away. If you need a response right away, you’ve got to give ipilimumab/nivolumab. If you have brain metastases, you’ve got to give ipilimumab/nivolumab. There is more wiggle room now that those data are out. I knew about that wiggle room because of Jeff Weber and CheckMate.

Jason J. Luke, MD, FACP: Jeff, if I can just make a quick comment, too. When I designed that study for the low-dose ipilimumab in the second line, the rationale at the time was that we thought we had PD-1 plus X combinations that were going to look really hot and give us less toxicity. We haven’t really gotten there yet. I still hold out hope for a future where that would be true. One could even imagine with the ongoing studies of relatlimab or bempegaldesleukin or other novel molecules in the front line that that could still be a play, a PD-1–based nontoxic regimen that increases response rate. If you don’t get that very quickly, then you flex over to give CTLA-4 combination. We’re thinking into the future now, but that was actually the rationale when we designed that study back when. I’m still hopeful that someday, we’ll be able to get there with the idea we can limit the toxicity of ipilimumab.

Transcript Edited for Clarity