Sequencing Decisions and Multidisciplinary Care in Metastatic Melanoma

Transcript:Georgina Long, MD: In our institution, the factors that really play into this are volume of brain disease and whether they have extracranial disease. How many brain metastases do they have? How big are the brain metastases? We discuss it in a multidiscipline-retained meeting. We know the response rate with a single-agent BRAF inhibitor. We’re about to see the response rate with combination BRAF/MEK. We’ve got 2 or 3 ongoing studies looking at nivolumab/ipilimumab and nivolumab alone in brain metastases. We need that data to really help us, but it ends up being a multidisciplinary approach. So, in our institution, for example, if you have oligometastases in the brain, we would even consider nivolumab/ipilimumab in that situation—but only if the radiation oncologist and the brain surgeon are there ready with us. But, we’re talking very sub-centimeter and not symptomatic. Watch and see how you go. If it’s a little more, 10 mm to 15 mm, they’re BRAF-mutant, and for some who are hitting 15 mm or more, use targeted therapies.

There are no rules except to say that it’s driven by the volume, the size, the number, and the state of the extracranial disease. But it’s a multimodality treatment, and even if you start on targeted therapy and they’ve got multiple metastases, let’s say 10 to 15, you know that you’re probably going to end up doing either surgery or stereotactic radiation down the track. It’s going to be combination and sequencing just to keep them alive really for as long as possible.

Michael A. Davies, MD, PhD: Another question then is—and, again, I’m sure Georgina and her colleagues think about this and talk about this—whether or not it makes sense to start with targeted therapy as a debulking strategy and whether or not you can convert someone over to the scenario where you think immune therapy would work. And, again, it’s a place where, unfortunately, we just don’t have any data at this point from clinical trials. It’s actually very challenging to design that clinical trial. I think that’s another question we get asked very commonly about these patients.

Georgina Long, MD: And it’s not just about the brain, it’s for extracranial, too. Can you get things under control, symptoms under control, for a short period of time and then switch to immunotherapy? Again, it’s a data-free zone, we don’t have data to actually drive the decision making. We do know that patients with a very, very extraordinarily high LDH are not going to do well on anything. But can we bring it down with targeted therapy and then come in with immunotherapy, where they’ve got a more normalized LDH. Will that make a difference? It’s actually the subject of some neoadjuvant approaches in looking at sequencing to get the best tumor control. It’s a data-free zone, but it’s very provocative and very compelling, actually, to want to do that.

Robert H.I. Andtbacka, MD, CM: Back to the brain metastases again. As you said, Georgina, many of these patients if they are not symptomatic and they have low-volume disease, it appears to be reasonable to consider starting either with a potential combination, immunotherapy versus a BRAF/MEK inhibitor. Now, is there any concern if they were to develop symptoms and you have to do radiation for them, if you are either on immunotherapy or on a BRAF/MEK combination, in terms of the potential effect of that radiation on the brain?

Georgina Long, MD: Great question. Clinical experience and some larger case reports tell us that you can safely give radiotherapy in combination with targeted therapy. Also, you can treat bulky brain disease with just targeted therapy and then hold off your radiotherapy until you’ve seen things reduce a bit. So, we know that, from clinical experience, that is safe to give. The issue with the immune therapies is, does immune therapy combined, for example, with stereotactic radiosurgery, increase the rate of radionecrosis? There is a background rate of radionecrosis with stereotactic radiosurgery. That’s going to be answered with trials that hopefully will read out next year. In BRAF wild-type patients who start with ipilimumab/nivolumab who seem to have a response, but maybe 3 shrink, 1 grows—cut it out if it’s a size that neurosurgeon can cut it out and it’s not in an area of the brain that matters—what if I give stereotactic radiosurgery? Am I going to give them a 50% chance of getting radionecrosis, a 70% chance, or is it only 30% chance? That will be answered next year. But these are the questions we really need to understand. I must say now, when your hands are tied and people have brain metastases and you’ve got to manage it, you give it; you watch and monitor and treat expectantly.

Robert H.I. Andtbacka, MD, CM: Mike?

Michael A. Postow, MD: I just want to add that when we’re talking about radiation, I think we’re really specifically talking about stereotactic radiosurgery, and that’s an important distinction. Even in patients with a lot of brain metastases that may not be amenable to stereotactic radiosurgery, with the rise of the immune therapies that we have, particularly BRAF/MEK inhibitors, and their proven efficacy in the brain and emerging data about immune checkpoint inhibition in the brain, I find that for whole brain radiotherapy, we really need to be thinking about that as a subsequent type of a step and starting these patients with initial systemic therapy and/or potentially radiosurgery at particular time points in combination—understanding that we don’t have all the data we really want about the toxicities. I think that needs to be thought of firs, and that really whole brain radiotherapy is moving to the background. And I would say we really only want to think about that after we’ve tried all these approaches, particularly if a patient is very well controlled in the extracranial compartment.

Michael A. Davies, MD, PhD: I guess one other point to this though is, again, with Mike Postow here talking about this possibility of radiation therapy potentially boosting the efficacy of immunotherapy. And so, this idea of if you had a patient that you’re treating with immune therapy, is there any rationale where you look to actually try to find a lesion that would be amenable to radiation to try boost to your immune responses, as you described in a very notable case report?

Michael A. Postow, MD: So, it’s an interesting idea, I would say. The theory is that if you radiated a tumor, would that cause some magical anti-tumor effects that would then potentially synergize with checkpoint blockade? And I would like to be very clear that we have no proof in patients yet that radiation increases the efficacy of checkpoint blockade. I would say that we should not be radiating tumors with the idea that we’re doing that to increase the efficacy of checkpoint blockade. That is information that we would need from a randomized trial, which, unfortunately, we don’t have yet. So, if a patient has a need for radiation anyway, I think it’s justified because they have a need for radiation anyway. And retrospective series suggested it may be safe to do that. But we don’t have prospective data to suggest, in patients, that radiating something increases the efficacy of checkpoint blockade. That has been shown in mouse models, and we’re hoping that it may be true in patients. But we’re not to that point just quite yet. So, it’s really about radiating people who have a need for radiation anyway.

Georgina Long, MD: I’d agree with that. And just talking about prospective data, there are retrospective data that suggest that radiotherapy combined with anti—PD-1 to the site you give radiotherapy—and it’s only in areas that need it, so progressing lesions—has a much higher response rate than what you would see with anti-PD-1 alone or in those who are progressing on PD-1 and then you irradiate. They have a nice response rate, only 40% in progressing lesions. However, the abscopal effect of other tumor sites, other metastatic sites shrinking, we have not seen that in the clinic. But certainly, the site of radiotherapy does have some synergies clinically only at that site.

Michael A. Davies, MD, PhD: One of the relevant clinical scenarios is that we’ve seen patients, whether they’re responding to targeted therapy or immunotherapy, present with an isolated lesion that’s progressing and, again, the brain being a common site for this and the brain being a place where we often will use something like stereotactic radiosurgery to treat that lesion. But if the other lesions are responding at that point, it’s very reasonable to continue that treatment even though, technically, patients have responded in the brain. We’re still trying to understand why this happens. But there can be potentially a different biology and immunology of melanoma in the brain versus other places in the body. This is an area that is in desperate need of both translational and clinical research. But this idea of whether we need specific therapy specifically to control melanoma once it’s spread to the brain, which may be distinct from what you need to control it outside the brain, is still an open question.

Transcript Edited for Clarity