Thomas Powles, MD: What are we doing with brain metastases? I saw a patient a few weeks ago with brain metastases. I gave VEGF TKI/IO [tyrosine kinase inhibitor/immunotherapy] therapy, and it didn’t work well. I don’t know if I should be surprised by that. Have we got enough data in brain metastases? Do we know what we’re doing?

Ulka Nitin Vaishampayan, MD: This is one huge hurdle, that brain metastases have been so underrepresented in all of the clinical trials. Most of these studies, the big phase 3 randomized studies that we are quoting, did not include patients with brain metastases. For that disease though, the systemic component as to how to get responses with systemic therapy, in my experience and there are data reported that showed that cabozantinib single agent did have efficacy, even in patients who were not receiving local therapy such as radiation to brain metastases, or if they were progressing past even post-radiation.

Thomas Powles, MD: Do you think immunotherapy does anything for brain metastases? Do you have any evidence that immunotherapy is doing anything for brain metastases? We can open this up to anyone.

Ulka Nitin Vaishampayan, MD: There is a small study of nivolumab, for instance, but the responses and the long-term outcomes are limited in that study.

Thomas Powles, MD: Would anyone else like to make a comment?

Rana McKay, MD: The NIVOREN study that was run by Laurence Albiges, [MD, PhD,] did demonstrate some activity, but I do think that RCC [renal cell carcinoma] is not the same as melanoma where we’re seeing some responses with IO therapy in the brain. The best data come from that NIVOREN study, the cabozantinib retrospective data, showing disease activity in untreated small brain metastases. But these are somewhat retrospective; there’s a huge bias there.

Benjamin Maughan, MD: One last comment about the brain metastases. There are some data to suggest that these systemic therapies have activity, but my perspective is that none of them have a response rate high enough that I think they should supplant definitive therapy of surgery or radiation. That’s how I approach it.

Thomas Powles, MD: Ben, your approach, let’s start with my patient who I saw a few weeks ago. He had quite widespread disease, he had intermediate nonporous disease. He had 2 brain metastases, they were asymptomatic, but were 1.5 and 1 cm with some edema around them. We spoke to radiation oncologists, he could have stereotactic radiation, that’s what they said to us. There was an issue about whether we should start therapy immediately. I wanted to start therapy, of course, he had widespread disease. They weren’t super unwell, but they had intermediate-risk disease. How do you approach this patient? Are you going off the brain with stereotactic radiation first, or are you saying we’ll start with systemic therapy, get control, and then have a discussion about radiation?

Benjamin Maughan, MD: It can be quite challenging because you have these effectively 2 separate problems, because our systemic therapies don’t consistently penetrate and control brain metastases. You have to balance both of them and which is putting the patient at greater risk. What’s the visceral crisis, their brain metastases or their extracranial disease? I readily think of 2 patients I had. One of them had disease everywhere that was growing very quickly. He had a lot of skin, cutaneous growths as well, which from my experience, are usually bad. However, he also had a lot of dural metastases that were encroaching on his cranial nerves. We started with treating his brain, and then I very quickly started him on a TKI/IO combination. In contrast, there was another patient who only had, similar to your patient, 2 brain metastases, but they were really small. They were less than 1 cm. It was hard to say, are these truly brain metastases, or are these artifacts of something else, microvascular disease or something? We opted to start systemic therapy, and then sure enough, within a month he came back to the ED [emergency department] with neurologic deficits, and they [the brain metastases] had grown. Trying to prioritize what to do depends on a lot of clinical judgment, which means we get it wrong sometimes.

Thomas Powles, MD: Let’s switch to the sarcomatoid data, which look fantastic, as I see, for all 4 regimes. It’s transformative, perhaps the best data we have in front of us. Why do you think that those patients are doing so well? Is there a specific regime you like to give?

Benjamin Maughan, MD: Out of all of the biomarkers that we have, predictive biomarkers that have been tested and investigated, this is probably the best biomarker. It’s not particularly helpful, as you allude to, in helping us choose between the IO therapy combinations, because each of them have shown that the response rates are high. But it clearly demonstrates that some immune therapy approach is important for these patients. It performs best as a prognostic marker in terms of its clinical utility. I tend to prefer giving ipi-nivo [ipilimumab plus nivolumab] to these patients unless there’s some pending visceral crisis because their response rates seem to be higher than the…patients who received ipilimumab and nivolumab in the CheckMate-214 study. Why these patients have a higher response rate, the specific mechanism, is something we still don’t fully understand. At least when I’ve reviewed the data, it doesn’t completely make sense to me. We still need to understand molecularly what’s different about that because remember, sarcomatoid differentiation, it’s just that. It’s not a distinct histology. It’s a differentiation that can be present with any of these histologies. Molecularly what’s unique about that differentiation pattern that renders it susceptible to immune therapy is something we really need to understand.

Thomas Powles, MD: Exciting, and perhaps we can learn something about the biology of those to help in the other cancers. Let’s come to quality, Eric.

Eric Jonasch, MD: I think we do know a little more about the microenvironment there, that gives us an idea. One of the things, a number of years ago, we presented these data looking at presurgical treatment, sunitinib-treated samples from patients who underwent nephrectomy and underwent systemic therapy afterward, demonstrating that those individuals who had increased T-cell ingress into the microenvironment ended up doing worse. Also they had upregulation of PD-L1, which makes sense because you have a T cell that comes in, it’s secreting interferon gamma and makes the tumor angry. You get counter-regulatory mechanisms. Sarcomatoid is that on steroids. You have a very large number of T cells in the microenvironment, you have the tumor cell that is very good at counter-regulating. You have this battle royal that’s occurring, which is making the patient feel terrible, but you have this immune system that’s locked and loaded. You come in with checkpoint blockade and those T cells, the effector T cells, then finally can function, and they’re ready to go. I think that’s why you’re seeing these dramatic responses. Survival for these individuals has gone from 6 to 12 months in the TKI era, where you weren’t able to unleash the immune system, now to having a CR [complete response] rate of 18% with ipilimumab and nivolumab. I think it’s a beautiful example of at least tissue biology that explains the clinical responses we see.

Thomas Powles, MD: I had a young man with advanced sarcomatoid disease. He made a lot of money, and gave up his job, and was preparing for his death. He’s now gone back to work 2 years later, and he’s more dynamic than he was before. It’s an extraordinary transformation.

Transcript edited for clarity.