Prevalence and Clinical Significance of Central Nervous System (CNS) Involvement in Non-Small Cell Lung Cancer (NSCLC); Indications for Various Local Treatment Modalities

DR GUBENS: Dr Gomez, why don’t you tell us what you can about various local treatment modalities?

DR GOMEZ: Okay, thank you for allowing me to speak on this topic today. And I’m going to be primarily covering the local treatment modalities in this scenario. And 2 primary goals of the talk: the first is to look at the various local treatment modalities, and the second is to look specifically at whole-brain radiation therapy, the potential long-term sequelae and approaches to mitigate these effects.

I’ll be covering primarily 4 areas: corticosteroids and best supportive care, surgery — systemic therapy I’ll leave to the other panelists — whole-brain radiation therapy and then a few recent innovations to attempt to improve on some of these side effects from whole-brain treatment.

A very important study, while it doesn’t necessarily come to mind immediately, is evaluating the use of best supportive care plus dexamethasone in patients that can’t receive stereotactic radiosurgery or surgery in the setting of brain metastases. And this was the QUARTZ trial that was published about 3 years ago now, that looked at 538 patients that were randomly assigned to either whole-brain radiation therapy or best supportive care with steroids. And with a primary outcome of quality-adjusted life years, interestingly did not find significant differences between the two. I’m presenting this study today because I think it brings home the point that best supportive care is an option for many patients with non-small cell lung cancer that aren’t amenable to these approaches.

On the other end of the spectrum is surgery. There are 2 studies that demonstrated the role of surgery several years ago, and we extrapolate many of these same themes into our practices today.

The first is the Patchell study of 1990 that demonstrated that patients that received surgery in the setting of a solitary brain metastasis did better than those that received whole-brain radiation therapy and biopsy only, with regard to overall survival. And the second looked at surgery plus or minus whole-brain radiation therapy in the setting of a single brain metastasis. And this is sometimes called the Patchell 2 study.

Now, interestingly, the primary endpoint of this study was brain control, and it did demonstrate a benefit here, but I think the more notable point is, there wasn’t an overall survival benefit with the use of whole-brain radiation.

However, as a result of this study, we extrapolate some of our stereotactic postoperative indications for this benefit in improving outcomes in that way while reducing some of the whole-brain radiation side effects.

When we look at whole-brain radiation therapy as a whole, as an adjuvant treatment with surgery, what we typically have found is that whole-brain radiation therapy does indeed reduce intracranial failure and local failure, but it doesn’t improve overall survival.

What’s the tradeoff with whole-brain radiation? I think that we see that adjuvant whole-brain radiation therapy can reduce quality of life. On the left we see global quality-of-life scores in patients that receive whole-brain radiation therapy adjuvantly, and particularly at 9 months, they’re reduced. And when we look at cognition on the right, cognition quality-of-life scores are reduced in those patients that received whole-brain radiation therapy.

And there are low- and high-grade toxicities associated with this treatment. Lisa DeAngelis, who is now the Physician in Chief at Memorial Sloan Kettering, published this paper 30 years ago showing the severe post-treatment effects that can occur with patients with whole-brain radiation, including dementia, ataxia and urinary incontinence. However, many of these patients received hypofractionated treatment courses with higher fractionation regimens that we would typically use today.

We don’t commonly observe these side effects in the modern era, but what we do see are other quality-of-life more subtle effects, but which can indeed reduce these patients’ quality of life. And these include social functioning, some nausea/vomiting, appetite loss and I think most significantly is that of cognitive decline and memory loss.

And these are several different tests that are used to measure memory loss, and you can see that they consistently demonstrate reduced memory loss in the setting of whole-brain radiation therapy. This particular study looks at PCI.

When we look at the short- and long-term side effects of whole-brain radiation therapy, what I typically tell patients — or I list the side effects on the left of alopecia, fatigue, mild dermatitis and acute worsening of symptoms, as well as a potential for a little bit of ear pain. But the most common side effect that we discuss, and the one that brings most discontent, is the reduction in short-term memory. And what I’ll tell them is, if I give them a list of things to remember right now — telephone, table, chair, et cetera, and they can repeat back 8 to me, afterwards it’s more common for them to be able to repeat back 6 or 7. More less-subtle deficits but those that typically are noticeable.

When we look at stereotactic in this setting, we see a similar paradigm in terms of the outcomes that we see when compared to whole-brain radiation therapy. We see reductions in intracranial failure, but we see no differences in overall survival. The graph on the left demonstrates reductions in intracranial failure, as does the top graph on the right, with the bottom graph demonstrating no differences in overall survival.

And when we look at several studies, we see similar themes. In the one column there we see surgical bed control, intracranial control improved, but survival the same. We can, I think, overall take from this that whole-brain radiation therapy improves intracranial control, not overall survival, and is associated with significant side effects.

My last couple minutes I’ll talk about a couple of approaches that have been used to mitigate these toxicities. The first is hippocampal-sparing radiation. The hippocampus is part of the limbic system. Us, as in many other animals, have 2 hippocampi, and they really play a key role in memory and the consolidation of short-term to long-term memory.

These are preclinical studies demonstrating the effect of radiation therapy to the hippocampus and affecting memory. The mice in these studies were given the test of the Morris water maze, which entails them finding a hidden exit from a maze. And you can see in the control group, after day 1, there’s a significant improvement in their ability to find this exit.
The number of seconds going down substantially, but in the control group this remains relatively constant.

I think even more compellingly, when neural stem cells are injected into mice where the hippocampus has been irradiated, you see restoration of some of this function. On the left we see the control group. In the middle we see the irradiated group, and on the right we see the mice that have been injected with neural stem cells. And these mice are tasked with remembering a certain object for a certain amount of time. The greater amount of time the better, and it’s improved significantly with the injection of neural stem cells.

And this is played out largely in clinical studies as well and has led us to integrate this hippocampal-sparing whole-brain radiation therapy technique, where it was done in a very systematic way where we contour the hippocampus and we then constrain this in a very stringent way to try to limit the dose to this structure.

When we’ve looked at clinical studies, they found that particularly with patients that live longer than 6 months, these functions can be restored. With those patients that die within 6 months, you continue to see this decline. This is why in the last question we generally don’t deliver it commonly for patients that receive whole-brain radiation therapy.

This said, the final approach that I’ll discuss is memantine. Memantine is a medication that works in the glutamate pathway. Glutamate targets NMDA, which is a primary receptor involved in learning and memory. While RT injury and ischemia inhibits this process, memantine inhibits the inhibitor, so therefore restores it. It’s used in other cases of dementia such as Alzheimer’s disease.

This was the landmark study looking at memantine that demonstrated a reduction in cognitive failure with those patients receiving whole-brain radiation therapy with the implementation of memantine given during and 6 months after treatment.

NRG-CC001 was then a follow-up on this study that combined these two techniques of hippocampal-sparing radiation and memantine and looked at cognitive failure in patients that received both of these approaches compared to those that receive memantine alone. And these results have been presented a couple of times and demonstrating attenuation of cognitive decline with the 2 techniques together versus 1.

I think overall we see that there’re multiple local therapy options that exist for patients with brain metastases, and risk stratification can help designate those patients for these approaches. Surgical treatment is a good option, with salvage SRS in the postoperative or salvage setting also being quite reasonable. Whole-brain radiation therapy is associated with a substantial number of side effects, particularly cognitive side effects, subtle but noticeable, and there are several strategies that are currently being implemented to reduce these side effects in the short and long term.

Thank you.

DR GUBENS: Daniel, I’m curious, what’s with the uptake of hippocampal-sparing approaches now that this has been published? Do you anecdotally feel like that’s really broadly had uptake? Is it pretty minimally used? Again, this panel doesn’t seem to use it much.

DR GOMEZ: Right. I think it’s definitely more common, and we saw the survey results bear that out to some extent. But I think that there still are these barriers to implementing them more widely.

Now, there’s a second study that’s being run, NRG-CC003, that’s looking at it in the PCI setting, and I think that if that is a positive study, then we would certainly see more patients with that approach getting this method. I think that we won’t run into these same constraints, because PCI isn’t as much time constrained as we often see in these patients with whole-brain radiation therapy. In addition, the prognosis isn’t as poor.

DR GUBENS: Great. Thanks, Dr Gomez.

Optimal Management of Brain Metastases in Oncogene-Driven NSCLC

DR GUBENS: Greg, why don’t you show us some of the data in this space. Really exciting stuff.

DR RIELY: Thank you, Dr Gubens.

When I started thinking about presenting this, I thought back to when I started all this 15, 20 years ago. And I think we had a very clear algorithm back then, say, and it really began with the idea that systemic therapies weren’t very good for the treatment of patients with non-small cell lung cancer. And so patients with brain metastases really should have received local therapy prior to systemic therapy.

And when we were thinking about local therapy, we thought if there was 1 lesion, maybe 2, surgery was the most appropriate approach. If there were 1 to 3 lesions, then you should do stereotactic radiotherapy. And if there were more than 3 brain metastases, everybody should get whole-brain radiation therapy. I think many of the people in the room remember those days. We gave a lot of folks whole-brain radiation therapy, which led to a lot of questions about how we manage whole-brain radiation therapy. How we reduce the toxicity. I think we think a little bit less about how to reduce toxicity of whole brain, because we spend a lot less time treating patients with whole-brain radiation therapy today.

What’s different today compared to when I started in this field is oncogene-driven cancers. We didn’t know about EGFR mutations when I was a fellow, and we now know that EGFR mutations exist, and we have good therapy to target EGFR mutations. But beyond EGFR there are a lot of other targeted therapy options. And we know about EGFR, ALK, ROS1. We’ll soon have FDA-approved therapies for RET. We have approved therapies for RAF. And these therapies are much better. And the therapies oftentimes have significant activity in the CNS, and so this really alters how we think about that.

I’ll begin by taking us through some data looking at EGFR as the paradigm of oncogene-driven non-small cell lung cancer. The most recent data we have that really looks at CNS activity for patients with EGFR-mutant lung cancer comes from this trial. This trial explored what the best first-line EGFR tyrosine kinase inhibitor was. Patients were randomized at initial diagnosis of EGFR-mutant lung cancer to either osimertinib or the standard of care EGFR TKI, which in this series was gefitinib or erlotinib.

This is the progression-free survival curve. This is the primary endpoint of the trial. And we see that with osimertinib, there is a significant improvement in progression-free survival. And you see that median progression-free survival here is 19 months, so really an excellent disease control and excellent duration of control for patients. We all get excited about this curve. It’s always sobering to remind everybody that if you look out there at 2 years, though, 60% of patients have progressed. We still need to do better than this, but it really shows us that osimertinib can be effective for these patients.

And moving further, we have the overall survival data, which was just actually published in The New England Journal of Medicine a couple days ago and recently presented, and you see that median overall survival for patients who received osimertinib was over 3 years. That first slide I showed, which showed how we approach patients with brain metastases, didn’t have any therapies for non-small cell lung cancer with median overall survivals of 3 years. Clearly a different thing.

But one of the really key things that we’ve learned about osimertinib is that it’s not only active in the whole body, it’s active in the CNS as well. And this is a series of 3 progression-free survival curves. The first progression-free survival curve, on the left, is the intention-to-treat analysis, which I’ve already shown you. Shows a median progression-free survival of 19 months. The middle panel shows those patients who had CNS metastases, and you see that while the median progression-free survival is a bit shorter, it’s clearly still better than the standard-of-care EGFR TKI. And the hazard ratio for the patients with CNS metastases in the middle, and the hazard ratio of the patients without CNS metastases on the right is exactly the same, showing us that osimertinib is as effective in the CNS as it is with systemic disease.

Looking at it a little bit more in a granular way, these are waterfall plots of the CNS disease in patients who are on this trial. And you see that, as we all knew, gefitinib and erlotinib, the standard-of-care drugs, they have activity in the CNS. They’re clearly CNS-active drugs, but on the left you see that osimertinib is better. We see deeper responses. We see more partial responses in the CNS. And it shows us that osimertinib is clearly superior to gefitinib or erlotinib in the CNS.

That’s EGFR. What about the other clear oncogene-driven cancer, ALK? And this is data from a similar trial, where we explored what the best first-line ALK TKI is. And I’ll show you 2 different trials that explored this, where the first-line TKI was either crizotinib or a second-generation ALK TKI like alectinib or brigatinib.

We’ll begin with alectinib. This is the so-called ALEX trial that compared alectinib to crizotinib. This is the progression-free survival data. This was the original presentation, and you see in this slide that the median progression-free survival had not yet been reached for patients who received alectinib, while the median progression-free survival for crizotinib was around 10, 11 months, which is exactly what we expected. The median progression-free survival has now been reached in an investigator-assessed level. The median progression-free survival is around 3 years. Really excellent performance by alectinib.

Alectinib is also very effective in the CNS. And this is a different way of looking at CNS activity, and this is the cumulative incidence of CNS progression in patients on this trial. And what you see in the red is those patients randomized to crizotinib. And you see that their CNS progression rate is markedly higher, where if you look out at 1 year, 41% of patients randomized to crizotinib had progressed in the CNS. By comparison, those patients who received alectinib, just 9% had progressed in the CNS. Clearly, definitely better to receive this second-generation ALK TKI compared to crizotinib.

Similarly, there’s a trial that looked at a drug called brigatinib. And this trial was a little bit later in its presentation, maybe a year later, but it’s similar. We see marked improvement in progression-free survival for brigatinib compared to crizotinib. Their hazard ratios are almost exactly the same, showing us that brigatinib is an improvement compared to crizotinib for the overall patient.

But what about CNS? We have a CNS progression-free survival curve. Again, you see that brigatinib is clearly superior to crizotinib in patients who have ALK-positive lung cancer in terms of CNS progression. Once patients have progressed on alectinib or brigatinib, they oftentimes progress in the CNS, and we have a recent approval of a drug called lorlatinib in this space.

Lorlatinib, if you look at that structure, it’s clearly funny looking, but that structure was designed to be a CNS-penetrant drug. This is a third-generation ALK inhibitor. It also hits ROS. It’s designed, as I said, not to be subject to drug efflux and penetrate the blood-brain barrier, and it was recently FDA approved.

It was recently FDA approved based on a series of patients, a small Phase II trial that looked at patients who had received either crizotinib and another ALK TKI, so the panel on the right, or just 1 ALK TKI. This is the activity of lorlatinib in patients with CNS disease. And you see, each bar represents an individual patient and their best response. And you see that this drug can be very effective for patients with CNS metastases, even when they’ve had prior second-generation ALK inhibitors.

I just wanted to take a minute to address some of the other modalities that can be used. And
a number of my colleagues from Memorial Sloan Kettering were co-authors on this paper, and this is a retrospective series that looked at a large number of patients who had oncogene-driven cancers and looked at their outcomes based on whether they received up-front stereotactic radiotherapy, up-front EGFR TKI or up-front whole-brain radiation therapy. And when you look at this curve, it’s pretty clear that in terms of overall survival, the patients who do best are those patients who received up-front stereotactic radiosurgery.

I just want to take 1 second to say why I don’t know that this applies to all our patients. I will say that this is data from the pre-osimertinib era, and so these patients would have received gefitinib or erlotinib, and so maybe that’s a substandard agent, and that’s part of this. But it’s also an interesting group of patients that were collected for this analysis. I won’t go through all the baseline characteristics, but I will highlight one, which is extracranial metastases at the time of brain metastasis.

This is the patients that were explored in this analysis. And what you see is that three quarters of patients had CNS-only disease. I think if you’re exploring what to do for those patients who have CNS-only disease, by all means, stereotactic radiosurgery is the right approach. But this data doesn’t apply to our vast majority of patients who either present with systemic disease and brain metastases or who develop brain metastases during the course of their care.

And I’ll just quickly note that stereotactic radiosurgery is not without its side effects. This is work put together by Zach Kohutek when he was still at Memorial, along with Kathryn Beal, and this looked at the incidence of radiation necrosis after stereotactic radiotherapy. I think as we do better with systemic therapy in patients with non-small cell lung cancer, we see patients live longer, and we encounter some of these difficult side effects later on in the course of their illness.

I wanted to highlight 2 things with this. One is, if you look at the X axis, the frequency or the incidence of radiation necrosis goes up over time, so the more we keep these people alive, the more likely they are to get radiation necrosis. And the size of the lesion increases the risk of radiation necrosis. If we address small lesions with stereotactic radiosurgery, the risk of radiation necrosis is small. But the bigger these lesions get, the more we waste time doing something else before we give stereotactic radiotherapy, the more we run the risk of radiation necrosis.

Just to conclude, I think given the current CNS and systemic efficacy of many tyrosine kinase inhibitors, it’s reasonable to defer initial radiation therapy for patients with brain metastases. I think developing drugs with simply better activity as well as better ability to cross the blood-brain barrier has improved outcomes for our patients with oncogene-driven cancers. Radiotherapy for brain metastases can lead to radionecrosis, and it’s something we have to keep in mind, because this increases with the size and how long our patients live.

Thank you very much.

Management of Leptomeningeal Metastases in NSCLC with a Targetable Tumor Mutation; Role of Immune Checkpoint Inhibition in the Treatment of CNS Disease Stemming from NSCLC

DR GUBENS: With that, I’ll hand it over to Dr Ahluwalia, and tell us about leptomeningeal disease and checkpoint inhibition.

DR AHLUWALIA: Thank you for the kind invitation. I’ve been charged to talk about leptomeningeal metastases in non-small cell lung cancer with targetable tumor mutation, and I also was asked to touch upon the role of immune checkpoint inhibition in treatment of the same, brain metastases stemming from non-small cell lung cancer.

Leptomeningeal metastases in non-small cell lung cancer, we actually truly do not know what the true incidence is. Because some of these patients get this when they’re close to their hospice, when their performance status is low. A lot of times they actually go undetected. But the various incidence has been described 3% to 10%. We know as we have done better with that care of systemic disease there’s a greater incidence of brain metastases, and I think similarly there’ll be a greater incidence of leptomeningeal going forward.

Prognosis typically — your usual treatment was pretty dismal — was 4 to 6 months, for the most part. Ten months would be more in the oncogenic-driven tumors where we have better therapies. We could even do pulsatile dosing therapy. And then, unfortunately, these patients progressed and they died. There was roughly a breakdown between leptomeningeal progression or combination of leptomeningeal progression and systemic progression and a smattering.

And sometimes, actually, when you really look at these reports, you don’t know what’s going on. Like, if the patient’s actively declining, you don’t know what’s the cause of decline. But there’s basically a mixed progression.

And with Mike Glantz in the audience, as I said, who’s done a lion’s share of work with intrathecal chemotherapy — and this is a very busy slide — but we know that when most of these trials were done, and most of them focused on lung cancer and breast cancer, at least in solid tumors, the takeaway is (a) that most of these were small studies, 20 to 30 patients, and (b) the median survival was in the ballpark of 4 months. That’s pretty much what you get with intrathecal. We know you get better outcomes in lymphomatous meningitis- or leukemia-based leptomeningeal spread. But in solid tumors, typically, when we have leptomeningeal disease, the outcomes are fairly dismal until recently, and I’ll share some data.

And BLOOM was actually one of the first trials which really focused on oncogenic-driven tumors with leptomeningeal disease. And here it was basically a 21-patient study. The key inclusions criteria was patients had to have EGFR L858R or exon 19 deletion. They could have had a previous EGFR TKI, and most of these patients used to have the first generations, typically erlotinib or gefitinib, depending on what part of the globe you lived in. Decent ECOG status 0, 1 or 2. And osimertinib in this trial was actually given at 160 mg daily. And they had assessments in terms of adverse events. They looked at survival and looked at whether there was clearance of the CSF cytology.

More importantly, they also looked at neurological exam. Because one of the challenges in leptomeningeal disease is, if the neurological deficits set in, they are very difficult to reverse, typically.

What we found out — and this is, again, a busy slide — but let me walk you through this. Efficacy assessments were seen in 21 patients, and out of them 7 had confirmed radiologic improvement. This was almost kind of unheard of, at least with our systemic treatments or our intrathecal chemotherapies. They had 7 confirmed responses, which was 33%. We, actually, our chemotherapy was not doing that well even with brain metastases, leave alone leptomeningeal disease. This was pretty remarkable from that.

And then the other part which is very intriguing was the neurological status. If patients had normal neurological status to begin with, which was 11 patients, only 1 of those patients actually had a deterioration. A majority of the patients were able to maintain their neurological status. But what was even more intriguing was that in those patients who started with abnormal neurological status, which generally is very difficult to reverse typically in these patients, 5 of those patients, so half of the patients, actually had an improvement of their neurological status, which is a pretty stark finding at that timepoint.

And now this was an abstract presentation. We’ve not had a publication come out yet. But at the time of treatment — so the data may be more mature now — but when this trial was actually presented at ASCO a few years back, 15 patients were actually ongoing treatment at the time of the data cutoff. And 7 of them had been on treatment for more than 9 months. This was pretty much the upper edge of even overall survival of these patients before this trial came on.

There was a lot of excitement about use of osimertinib at a higher dose, and then more recently this data was presented with the other leptomeningeal cohort, which basically showed that the standard dose might actually work well too. There was preclinical data that you had a fair amount of blood-brain barrier penetration with even 80 mg compared to 160 mg. And here you can see a median progression-free survival of 11 months and median overall survival of 19 months. This was pretty dramatic improvement as compared to what the historical cohorts were, which I showed in my first slide.

Moving on, before we had osimertinib we used to have erlotinib, and one of the regimens which was actually championed out of Memorial, Mark Kris and people there, and Jenny Clarke when she was a fellow there, had published these case reports of high-dose weekly erlotinib actually having nice responses in, indeed, a select group of patients who had progressed on the standard dose of erlotinib. Because with erlotinib it does not have that good of a blood-brain barrier penetration, so if you give a higher dose, you do better.

Moving on — and Dr Greg Riely talked about ALK-translocated disease, so we actually have case reports of some of these agents, and he talked about how these alectinib and the next generation of drugs are working well in this patient population. This is a case report of a nice response with alectinib, which is, in fact, now a very commonly used drug in the up-front setting for these patients.

And this is ceritinib, which is, again, a new-generation drug with good blood-brain barrier penetration. More recently the data was presented at ESMO with ceritinib in even brain metastases. This is a case report of a patient actually getting benefit when they had a mutation at the ALK gene at codon I1171.

Next, moving on, there was a trial that was presented at ASCO last year. This is a Phase II trial of pembrolizumab, actually, in leptomeningeal disease. And pembro was given every 3 weeks here, and CSF was then sampled every 3 weeks as well. It was a study led out of MGH, and what they showed was that median overall survival was 3.6 months, which was not too much different than what we are used to seeing. But again, we typically don’t use pembro in oncogenic-driven tumors, as we said, so this was wild type, which we know typically don’t do as well. They generally have more progressive or fast-growing disease.

Moving on to what’s the data with immune checkpoint blockade in non-small cell lung cancer, this was a study led out of Yale, with Sarah Goldberg and Harriet Kluger, and this had 2 components. One was the non-small cell arm, and one was the melanoma arm. And what was very interesting to see was actually there was a 33% response rate in non-small cell brain metastases, so initially when they presented this there were 18 patients in the non-small cell cohort, where 6 of them at least had either a PR or a CR.

And this was ongoing, and then, actually, Sarah Goldberg presented updated data, and the manuscript is going to come out fairly soon, where she actually expanded this cohort from 18 patients to further. And what she showed was that those patients who had PD-L-positive disease were those who were getting benefit. And here in a little bit more expanded cohort you see 30% response rate, and that’s what we’re used to seeing in most of the studies using a single checkpoint blockade in lung cancer.

And again, there was a duration of CNS response. We do know when these patients do get response with the checkpoint blockades, they typically tend to be a little bit more durable. But again, we are waiting for more updated data, which will probably be there in the manuscript in the next few months.

Then at Cleveland Clinic we do a fair amount of stereotactic radiosurgery. This is retrospective data, but when we looked at how we were doing with the sequencing, because we do know that radiation can actually act as a neoantigen approach, where it can act as a vaccine, almost, so there is synergy. Abscopal effects have been described as well.

We looked at over 150 patients who underwent stereotactic radiosurgery to over 1,000 lesions, and these patients also received immune checkpoint blockade. And what we found out was that those patients who had gotten immediate immunotherapy, which was defined as less than 1 half-life of the immunotherapy, along with SRS, we had very nice responses. As you can see, a very nice high rate of complete responses compared to those who did not get immune checkpoint blockade immediately. Where there was a fair amount of complete responses, which we know can come from stereotactic radiosurgery used alone. Something to consider, and we are now focusing on the next cadre of trials, where we are going to look at the interplay of stereotactic radiosurgery with immune checkpoint blockade.

What we also found in this trial, as I said, there was a fair number of patients who got CR, but getting a CR matters, because as you can see, there’s a very nice dichotomy of survival on those who get a CR compared to those who have a PR or stable disease.

I think we should go for doing better with our patients as they’re living longer, and what is also interesting is what the Memorial group had earlier reported, the lung cancer cohort. The same thing is happening in brain metastases. If they’re on steroids, they don’t do well compared to when they are not on steroids. Despite representative of the fact that it’s a more aggressive disease, but we do know steroids are immunosuppressive, and if patients are on steroids for the first 4 weeks before getting SRS, immune checkpoint blockade in brain metastases, we know they do poorly.

This is a recapitulation of the clinical trials. Now, this is entire CNS metastases. We know the bulk of the work is actually being done in melanoma, where we know a combination checkpoint blockade may work better than a single checkpoint blockade. But the jury’s still out there. We had a New England Journal of Medicine paper recently on nivo/ipi, but most of the trials, at least in brain mets, have so far been with pembro alone from the Yale group.

But what is very interesting to note is, there is a lot of interest in immunotherapy, and as you can see, there’s a long list of ongoing brain metastases clinical trials using immunotherapy either alone, using various combinations or, more importantly, looking at the interplay of combination of some forms of radiation, and our approach is to use more focused forms of radiation, like stereotactic radiosurgery, when we try to combine it with immune checkpoint blockade.

Thank you so much.