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Thank you very much to the organizers for inviting me. It's very exciting to be here. We're gonna change topics a little bit and not talk so much about technique or whether or not...how we do our radiosurgery but more how we get into the big picture of the oncology world.
And so, as you heard a little bit from Dr. [inaudible 00:00:22] and Dr. Asher [SP] this morning, we have new kids in the playground. They have expensive but very effective tools for treating cancer. And...sorry. And so, from the patient standpoint, immunotherapies and targeted therapies have revolutionized how we treat cancer, things like melanoma, lung cancer, renal cell cancer, some of the more difficult cancers to treat. Patients are not as sick. They're actually living longer. And so, what does this really mean for us? Well, what it means is that because people...patients are living longer, they're more likely to get brain metastases and so we need to be part of this discussion. But also, that we need to be aware that many of these agents cross into the brain and their efficacy is being demonstrated a lot by medical oncologists.
All right. And so, what is the right treatment paradigm? Where do we fit in? I think it's important for us to pay attention to toxicities and efficacies on our side as well as theirs. But I think one thing that's really important for us to understand is that immunotherapies and targeted therapies are actually completely different. And this may be an oxymoron for some of you in the audience but for me, when I started, I did not understand this.
All right. So, let's start with immunotherapy. So, I went online on the NIH and looked at the clinical trial site and looked to see how many immunotherapy studies there are today. And there are over 2,000. For brain metastases more specifically, there are less but what you have to understand is that the medical oncology field is feeling like for the first time they can use drugs to take care of brain metastases by themselves.
All right. And so, what's different about these clinical trials is the exclusion criteria. So, when I first started, if you had an untreated brain metastasis, right, you were excluded from clinical trial and they came to us, we treated them, then they went back and got whatever they could get. That is no longer true today, all right. Many of these trials are interested in what their drugs can do in the brain. So as long as the patient has small asymptomatic brain metastases, they will just get drug and they won't come to us. And so, it's really important for us to understand where we stand with this.
All right. So, to understand where we stand, let's have a look and see what immunotherapy alone can do for brain metastases. And so, these are a couple of patients from our trial that we started in 2014 looking at this. So, this first patient is a 56-year-old lady with BRAF-mutant melanoma. You can see over here that she had multiple small brain metastases that were slowly but inadvertently progressing on her BRAF inhibitor. These lesions were small, however, and certainly the [inaudible 00:03:29] scan did not suggest that there was a lot of flare around these lesions. And so, it was our first patient. I was like, "Okay. Maybe." So, they started...so she started and unfortunately, after her second dose of immunotherapy, she came in with severe headache, lethargy and you can see the scan here. So, this was her scan. The lesions are clearly looking a little bit bigger and fuzzier around the edges. And then this scan here which was much more worrisome for me which showed a lot of edema in the brain. So, what is our first response to that? Well, it's to give steroids, all right. But our medical oncologists were adamant that steroids were not the right thing to give because that was gonna be completely anti-immunotherapy in effect.
So, we struggled with some mannitols and diuresis, you know, and managed the patient that way. And what was really interesting about that conversation was their interpretation of this scan which was that this was in fact not progression which is what I thought it was but this was in fact pseudo progression because immunotherapy causes inflammation in the brain and this is inflammation, right, in the brain. And despite the fact that I was trying to argue that this was not working, the alternative argument was that, "Well, immunotherapy takes a little while to work, all right." And that is true in the body and it can also be true in the brain. Unfortunately, while we were having this argument, the patient herniated and died. And so, my lesson was absolutely use steroids if you need it. It doesn't matter what your medical oncologist says. And I think it's really important to pay attention and be strong about your argument about progression.
All right. Before our first patient died, however, we enrolled this patient. So, this is our second patient. He's 91 years old with BRAF wild type melanoma. He had new...this new asymptomatic lesion on his MRI brain. Interestingly enough, you will see that he has a lot of edema around his lesion. And so, we were a little bit worried again about giving him immunotherapy but this is a very superficial lesion. I can resect it, I can salvage this patient and so we let him go on trial. And so just to bring the point home. And so, he obviously tolerated immunotherapy very well. He's had a very nice response to immunotherapy with his intracranial lesion but what you can see is that the edema has also gone away, all right. And so, it is my experience in fact that if your lesions are getting bigger and the edema is getting worse, it is progression, not pseudo progression, all right.
All right. Third lesson. It was a very hard trial for me. So, this is a 42-year-old gentleman who's had an excellent control of his systemic disease, has actually had local therapy several times in the brain and then developed this new lesion in his...on his MRI. Very little edema around it. He starts on trial. And then within two weeks, he actually has a seizure, has a scan that looks like this. We're still having that debate whether or not this is progression at the time. And then by four weeks, he hemorrhages, you know, and so now we've turned what was a radiosurgery, amenable lesion at the beginning to something that required surgery and larger field salvage, all right.
And so, one of the things that we have very little experience with is what happens if we don't treat these patients, right. These patients come to us, we treat them right away and then they go on and get other treatments and we don't have to worry upfront. But so particularly with melanoma, though, it's very important to be aware that these can progress very, very quickly.
All right. So, after all those really painful lessons, we came to an agreement that said that if I was uncomfortable, we would go ahead and give local therapy and then we would go on trial. And so, this was our fourth patient. And so, what you can see here, this patient had these three lesions. This one, this one and that one. Obviously, I felt uncomfortable with this first one because it was large and had some edema around it so I resected it. We then went ahead and gave radiosurgery to the post-op cavity as well as the lesion adjacent to the brain stem because if we bled there, that would be a problem. And then we allowed this one to go on trial.
And six weeks later what's really interesting is amazing, local therapy still works really great. All right. And so, I think it's important as Dr. [inaudible 00:08:05] said before, it's really important to weigh what the efficacies are of the different agents that you're treating, all right. And so, what's even more interesting, though, is that even though this patient is progressing obviously on immunotherapy, we've actually had an incredibly good response here with radiosurgery and we'll talk about this in a minute.
All right. And so, lessons learned, that melanoma arm of the trial is completed. We enrolled 23 patients. Six patients...oh, sorry. There wasn't a switch here. So, what the medical oncologists will quote to you is that these patients had a median overall survival of 17 months and 48% of these patients are still alive at 24 months which is amazing for melanoma, all right. What they don't tell you, though, is that of the 23 patients, only 6 actually had a CNS response to the immunotherapy alone, right. And so, when you break down the 23 patients, 7 patients never needed local CNS therapy but that's because 5 of them died so quickly. They never came to us. Seven were treated with some kinda safety maneuver at the beginning but five of those needed subsequent salvage and two of them died quickly. And of the nine that entered trial without some kind of safety maneuver at the beginning, all of them needed salvage local therapy, all right.
And so, it's really important to understand that this is...that we still play a significant role, all right. And so, our current institutional practice is that unless you're on trial, patients receiving immunotherapy should be treated with either radiation or surgery for their brain metastases up front.
All right. So going back, though, we did learn one other thing. And so, this is another patient that was on trial. As you can see, he had multiple brain metastases, many of which had hemorrhaged and so trying to put this guy on trial. He didn't have many other options. He had the whole brain radiation therapy already. And so, we agreed to give him radiosurgery salvage to some of the larger lesions before he went on trial trying to give him one last hope.
What was interesting, though, was...and so this is an example, this lesion here was one of the ones that we treated. And what was really amazing was that we only gave him 12 gray mainly because we didn't think he was gonna live very long but also because he was older and he didn't...we didn't want him on the treatment table for a very long time and felt we could salvage him with an additional 12 gray down the line if we needed to. But at six weeks, you can see what an incredible response he's had. And so, this is not just radiosurgery alone. This is radiosurgery plus immunotherapy, all right.
And so, we went back and looked at all of our patients on trial and not on trial and what you can see here is this is a graph of volume change after radiosurgery. So, time of radiosurgery is time zero and this is time after radiosurgery here. The yellow line is what we used to do which is radiosurgery not concurrent with immunotherapy. And the blue line that you can see here is concurrent. So, when you give immunotherapy with radiosurgery, you actually get a marked improvement in lesional response to radiosurgery.
All right. So, this is good. Obviously, the two are synergistic but the two are also synergistic in the long term, all right. And so, there are also negative interactions. So, 53-year-old lady who previously had radiosurgery several times without event who in April of 2014 developed this lesion. We gave it radiosurgery. It responded. She started pembrolizumab here as single agent and you can see less than one month later, the lesions started to regrow to the point where it was symptomatic, had to be resected. And interestingly enough, no tumor, absolutely no tumor whatsoever. All radiation effect.
All right. And so, I think it's pretty well known now that immunotherapy in conjunction with radiosurgery can also cause an increased risk of adverse radiation events. All right. And so, what's different, though, and it's important for us to recognize is timing, all right. So, timing can be as early as one month after radio surgery. This is a standard timing. So, a gentleman had this lesion resected, had the post-op cavity given radiosurgery, too, and you can see the radiation necrosis occurring at about the 12-to-18-month mark. But this patient also who got this lesion treated with radiosurgery and then this radiation necrosis three years later. And so, what you have to remember now is that unlike chemotherapy, immunotherapy, if it's successful in the body is a lifelong treatment, all right. And so those same complications that occur early can occur at the standard time and can occur way down the line. So, the latest I've seen this occur is about four and a half years out so far.
All right. And so unfortunately, we have...still don't have enough data for institutional guidelines for avoidance of radiation necrosis. I know we're all working on that. But what we have done is we talked to our medical oncologists and if they're gonna get concurrent immunotherapy at the time of their radiosurgery, then in fact we've been dose deescalating. And so, our standard doses have been 20 to 22 gray for melanoma and went down to often 18 gray and we've in fact used this to our advantage. We've not studied this systematically yet but moving down into the 15 gray range even with larger lesions with concurrent therapy and getting good results. So, I think this is something we should think about.
The lung cancer arm of the study just closed a month ago and so we don't have all the data on that yet. But what's interesting, though, is that the responses that we're seeing in melanoma may in fact not be the same as those for lung cancer. And so, what you can see here is the gray and the yellow lines are the melanoma lines out through three years showing that difference in response for concurrent and nonconcurrent therapy. But our blue and orange lines are our lung cancer lines for chemotherapy versus immunotherapy and it does not quite seem to be the same. And so obviously the guidelines for using immunotherapy together with radiosurgery may in fact become disease specific.
All right. So, I don't have a lot of time so I'll move on quickly. So again, immunotherapy and targeted therapies are different. Immunotherapy works on the body to identify cancer cells to get rid of them, all right, whereas targeted therapies work right on the cancers themselves and it's very important to recognize again that not only do they have...they're mechanistically different, but they also are effectively different, all right. And so, as we talked about with the immunotherapy, they have a slow onset but we're looking for a cure with those. We can give steroids if possible with these drugs as opposed to targeted therapies which are very, very quickly effective both in the body and the brain but they're rarely curative as Dr. [inaudible 00:15:13] had mentioned before and...but their CNS penetration is very, very good.
All right. And so...sorry. Oops. There we go. So, if there's any doubt that these drugs work in the brain, this was the example that taught me this. This is a lady who had ALK rearranged non-small cell lung cancer. She had no disease in her body but then presented with numbness in her hand. And she had this 5-centimeter lesion in her brain. We offered her surgery and whole brain radiation therapy all of which she refused and so they put her on a targeted agent and you can see in three weeks that she's down to 3 centimeters and continue to shrink, all right. And so, if these drugs work in the brain, then what is the role of radiosurgery?
Well, with melanoma, the answer's relatively easy. The problem with the melanoma drugs is that there's not very many of them, even for the BRAF target. And their failure rate is actually about 40% to 60% at a median of 3 to 6 months. So as Dr. [inaudible 00:16:14] showed an example of, once the drug stops working, then it regrows in the brain and so it's pretty easy to decide you should just go ahead and give radiosurgery for these patients.
In lung cancer, however, the argument is very different. So, the difference is that particularly for EGFR...so for ALK mutated lung cancers...I think probably many of us are not seeing this anymore because the drugs are so effective in the brain. For EGFR mutations, that's perhaps a little bit different but there are many, many, many drugs coming out for these diseases. And so, when the first one doesn't work, the second one gets started. When the second one doesn't work, the third one gets started. And they all have some efficacy in the brain which is why they may never come to us. So, the argument from the medical oncology side is that not only are there many drugs available and so they can use one drug to take care of everything and not take on additional toxicity from our local therapies but the median progression free survival from each of these drugs in an additive fashion, all right, can be in the order of 12 months. So, it could be three years before you see these people from the time of their original brain metastases.
The flipside of that. So, the argument from our side, though, is exactly the same as with melanoma, which is that these lesions can regrow the minute the drugs stop. And so, when you finally get to the end and you've run out of options, then don't be looking at us, you know, to help you out because that's a lot of lesions we gotta treat. And in all honesty, there's no additional toxicity to radiation and targeted therapies together.
And so, to try and work out where we fit in with all of this, we did a multicentered study and the results of this have been validated in many centers now around the world, looking...comparing TKIs, so targeted therapy for lung cancer only versus TKI plus radiation up front at first diagnosis of brain metastasis, and what was really interesting...and so I have to admit this was a very unexpected finding but that even in the radiation group, even though they had more symptomatic, larger...and a larger size and a larger number of brain metastases, you can see that intracranial progression was actually better controlled after radiation than it was with TKI alone. And not only that, but that in fact translated to an improvement in overall survival. And so, in the graph here you can see that the purple line is radiosurgery plus TKI versus whole brain radiation therapy with TKI in the blue and then...and TKI alone. And obviously, we don't necessarily understand why there is an overall survival improvement but it may be...and these people, they live long enough that progression free survival is the determinant.
All right. And so, our current institutional practice is if the patient is eligible for radiosurgery, then first line treatment of new brain metastases should be concurrent TKI and radiosurgery. If the patient needs whole brain radiation therapy because that's a never treatment now, then they go ahead and get drug first and then hopefully that can be salvaged for fewer lesions down the line. Obviously, at failure, though, salvage options are again individualized. And so, there are some...few randomized prospective trials out there looking at first line TKIs and comparing TKI only to TKI and radiosurgery but the problem is most of those studies have become obsolete because of this new drug, osimertinib.
And so, what you can see here in this PET study on monkeys is that the penetration of erlotinib and gefitinib which was first generation TKIs is really very little in the brain and that this new drug, osimertinib, has incredible and irreversible penetration into the brain. And so, there is a new randomized study now looking at this. And so, this may again change how we view radiosurgery in this population.
All right. So, in conclusion, treatment of brain metastases has gotten more complicated. It's not just us first, then them anymore, all right. We have to work with them. I think it's important to play on the playground together. It is important to be part of the discussion of what the patient's systemic therapy is because together, you may be able to do better. It is important to weigh the efficacy and toxicity of what we have to offer versus what they have to offer. These people are living a long time. They're gonna need all of us, all right, just at different times. And we need to participate in the clinical trials and the data collection. And so, the Brainlab, you know, system registry, sorry, for data collection is something that I encourage you all to participate in because the larger numbers we have, the better we will be able to study this and say exactly what role do we play.
And so, I think together we will do better for our patients. Thank you.
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Thank you very much to the organizers for inviting me. It's very exciting to be here. We're gonna change topics a little bit and not talk so much about technique or whether or not...how we do our radiosurgery but more how we get into the big picture of the oncology world.
And so, as you heard a little bit from Dr. [inaudible 00:00:22] and Dr. Asher [SP] this morning, we have new kids in the playground. They have expensive but very effective tools for treating cancer. And...sorry. And so, from the patient standpoint, immunotherapies and targeted therapies have revolutionized how we treat cancer, things like melanoma, lung cancer, renal cell cancer, some of the more difficult cancers to treat. Patients are not as sick. They're actually living longer. And so, what does this really mean for us? Well, what it means is that because people...patients are living longer, they're more likely to get brain metastases and so we need to be part of this discussion. But also, that we need to be aware that many of these agents cross into the brain and their efficacy is being demonstrated a lot by medical oncologists.
All right. And so, what is the right treatment paradigm? Where do we fit in? I think it's important for us to pay attention to toxicities and efficacies on our side as well as theirs. But I think one thing that's really important for us to understand is that immunotherapies and targeted therapies are actually completely different. And this may be an oxymoron for some of you in the audience but for me, when I started, I did not understand this.
All right. So, let's start with immunotherapy. So, I went online on the NIH and looked at the clinical trial site and looked to see how many immunotherapy studies there are today. And there are over 2,000. For brain metastases more specifically, there are less but what you have to understand is that the medical oncology field is feeling like for the first time they can use drugs to take care of brain metastases by themselves.
All right. And so, what's different about these clinical trials is the exclusion criteria. So, when I first started, if you had an untreated brain metastasis, right, you were excluded from clinical trial and they came to us, we treated them, then they went back and got whatever they could get. That is no longer true today, all right. Many of these trials are interested in what their drugs can do in the brain. So as long as the patient has small asymptomatic brain metastases, they will just get drug and they won't come to us. And so, it's really important for us to understand where we stand with this.
All right. So, to understand where we stand, let's have a look and see what immunotherapy alone can do for brain metastases. And so, these are a couple of patients from our trial that we started in 2014 looking at this. So, this first patient is a 56-year-old lady with BRAF-mutant melanoma. You can see over here that she had multiple small brain metastases that were slowly but inadvertently progressing on her BRAF inhibitor. These lesions were small, however, and certainly the [inaudible 00:03:29] scan did not suggest that there was a lot of flare around these lesions. And so, it was our first patient. I was like, "Okay. Maybe." So, they started...so she started and unfortunately, after her second dose of immunotherapy, she came in with severe headache, lethargy and you can see the scan here. So, this was her scan. The lesions are clearly looking a little bit bigger and fuzzier around the edges. And then this scan here which was much more worrisome for me which showed a lot of edema in the brain. So, what is our first response to that? Well, it's to give steroids, all right. But our medical oncologists were adamant that steroids were not the right thing to give because that was gonna be completely anti-immunotherapy in effect.
So, we struggled with some mannitols and diuresis, you know, and managed the patient that way. And what was really interesting about that conversation was their interpretation of this scan which was that this was in fact not progression which is what I thought it was but this was in fact pseudo progression because immunotherapy causes inflammation in the brain and this is inflammation, right, in the brain. And despite the fact that I was trying to argue that this was not working, the alternative argument was that, "Well, immunotherapy takes a little while to work, all right." And that is true in the body and it can also be true in the brain. Unfortunately, while we were having this argument, the patient herniated and died. And so, my lesson was absolutely use steroids if you need it. It doesn't matter what your medical oncologist says. And I think it's really important to pay attention and be strong about your argument about progression.
All right. Before our first patient died, however, we enrolled this patient. So, this is our second patient. He's 91 years old with BRAF wild type melanoma. He had new...this new asymptomatic lesion on his MRI brain. Interestingly enough, you will see that he has a lot of edema around his lesion. And so, we were a little bit worried again about giving him immunotherapy but this is a very superficial lesion. I can resect it, I can salvage this patient and so we let him go on trial. And so just to bring the point home. And so, he obviously tolerated immunotherapy very well. He's had a very nice response to immunotherapy with his intracranial lesion but what you can see is that the edema has also gone away, all right. And so, it is my experience in fact that if your lesions are getting bigger and the edema is getting worse, it is progression, not pseudo progression, all right.
All right. Third lesson. It was a very hard trial for me. So, this is a 42-year-old gentleman who's had an excellent control of his systemic disease, has actually had local therapy several times in the brain and then developed this new lesion in his...on his MRI. Very little edema around it. He starts on trial. And then within two weeks, he actually has a seizure, has a scan that looks like this. We're still having that debate whether or not this is progression at the time. And then by four weeks, he hemorrhages, you know, and so now we've turned what was a radiosurgery, amenable lesion at the beginning to something that required surgery and larger field salvage, all right.
And so, one of the things that we have very little experience with is what happens if we don't treat these patients, right. These patients come to us, we treat them right away and then they go on and get other treatments and we don't have to worry upfront. But so particularly with melanoma, though, it's very important to be aware that these can progress very, very quickly.
All right. So, after all those really painful lessons, we came to an agreement that said that if I was uncomfortable, we would go ahead and give local therapy and then we would go on trial. And so, this was our fourth patient. And so, what you can see here, this patient had these three lesions. This one, this one and that one. Obviously, I felt uncomfortable with this first one because it was large and had some edema around it so I resected it. We then went ahead and gave radiosurgery to the post-op cavity as well as the lesion adjacent to the brain stem because if we bled there, that would be a problem. And then we allowed this one to go on trial.
And six weeks later what's really interesting is amazing, local therapy still works really great. All right. And so, I think it's important as Dr. [inaudible 00:08:05] said before, it's really important to weigh what the efficacies are of the different agents that you're treating, all right. And so, what's even more interesting, though, is that even though this patient is progressing obviously on immunotherapy, we've actually had an incredibly good response here with radiosurgery and we'll talk about this in a minute.
All right. And so, lessons learned, that melanoma arm of the trial is completed. We enrolled 23 patients. Six patients...oh, sorry. There wasn't a switch here. So, what the medical oncologists will quote to you is that these patients had a median overall survival of 17 months and 48% of these patients are still alive at 24 months which is amazing for melanoma, all right. What they don't tell you, though, is that of the 23 patients, only 6 actually had a CNS response to the immunotherapy alone, right. And so, when you break down the 23 patients, 7 patients never needed local CNS therapy but that's because 5 of them died so quickly. They never came to us. Seven were treated with some kinda safety maneuver at the beginning but five of those needed subsequent salvage and two of them died quickly. And of the nine that entered trial without some kind of safety maneuver at the beginning, all of them needed salvage local therapy, all right.
And so, it's really important to understand that this is...that we still play a significant role, all right. And so, our current institutional practice is that unless you're on trial, patients receiving immunotherapy should be treated with either radiation or surgery for their brain metastases up front.
All right. So going back, though, we did learn one other thing. And so, this is another patient that was on trial. As you can see, he had multiple brain metastases, many of which had hemorrhaged and so trying to put this guy on trial. He didn't have many other options. He had the whole brain radiation therapy already. And so, we agreed to give him radiosurgery salvage to some of the larger lesions before he went on trial trying to give him one last hope.
What was interesting, though, was...and so this is an example, this lesion here was one of the ones that we treated. And what was really amazing was that we only gave him 12 gray mainly because we didn't think he was gonna live very long but also because he was older and he didn't...we didn't want him on the treatment table for a very long time and felt we could salvage him with an additional 12 gray down the line if we needed to. But at six weeks, you can see what an incredible response he's had. And so, this is not just radiosurgery alone. This is radiosurgery plus immunotherapy, all right.
And so, we went back and looked at all of our patients on trial and not on trial and what you can see here is this is a graph of volume change after radiosurgery. So, time of radiosurgery is time zero and this is time after radiosurgery here. The yellow line is what we used to do which is radiosurgery not concurrent with immunotherapy. And the blue line that you can see here is concurrent. So, when you give immunotherapy with radiosurgery, you actually get a marked improvement in lesional response to radiosurgery.
All right. So, this is good. Obviously, the two are synergistic but the two are also synergistic in the long term, all right. And so, there are also negative interactions. So, 53-year-old lady who previously had radiosurgery several times without event who in April of 2014 developed this lesion. We gave it radiosurgery. It responded. She started pembrolizumab here as single agent and you can see less than one month later, the lesions started to regrow to the point where it was symptomatic, had to be resected. And interestingly enough, no tumor, absolutely no tumor whatsoever. All radiation effect.
All right. And so, I think it's pretty well known now that immunotherapy in conjunction with radiosurgery can also cause an increased risk of adverse radiation events. All right. And so, what's different, though, and it's important for us to recognize is timing, all right. So, timing can be as early as one month after radio surgery. This is a standard timing. So, a gentleman had this lesion resected, had the post-op cavity given radiosurgery, too, and you can see the radiation necrosis occurring at about the 12-to-18-month mark. But this patient also who got this lesion treated with radiosurgery and then this radiation necrosis three years later. And so, what you have to remember now is that unlike chemotherapy, immunotherapy, if it's successful in the body is a lifelong treatment, all right. And so those same complications that occur early can occur at the standard time and can occur way down the line. So, the latest I've seen this occur is about four and a half years out so far.
All right. And so unfortunately, we have...still don't have enough data for institutional guidelines for avoidance of radiation necrosis. I know we're all working on that. But what we have done is we talked to our medical oncologists and if they're gonna get concurrent immunotherapy at the time of their radiosurgery, then in fact we've been dose deescalating. And so, our standard doses have been 20 to 22 gray for melanoma and went down to often 18 gray and we've in fact used this to our advantage. We've not studied this systematically yet but moving down into the 15 gray range even with larger lesions with concurrent therapy and getting good results. So, I think this is something we should think about.
The lung cancer arm of the study just closed a month ago and so we don't have all the data on that yet. But what's interesting, though, is that the responses that we're seeing in melanoma may in fact not be the same as those for lung cancer. And so, what you can see here is the gray and the yellow lines are the melanoma lines out through three years showing that difference in response for concurrent and nonconcurrent therapy. But our blue and orange lines are our lung cancer lines for chemotherapy versus immunotherapy and it does not quite seem to be the same. And so obviously the guidelines for using immunotherapy together with radiosurgery may in fact become disease specific.
All right. So, I don't have a lot of time so I'll move on quickly. So again, immunotherapy and targeted therapies are different. Immunotherapy works on the body to identify cancer cells to get rid of them, all right, whereas targeted therapies work right on the cancers themselves and it's very important to recognize again that not only do they have...they're mechanistically different, but they also are effectively different, all right. And so, as we talked about with the immunotherapy, they have a slow onset but we're looking for a cure with those. We can give steroids if possible with these drugs as opposed to targeted therapies which are very, very quickly effective both in the body and the brain but they're rarely curative as Dr. [inaudible 00:15:13] had mentioned before and...but their CNS penetration is very, very good.
All right. And so...sorry. Oops. There we go. So, if there's any doubt that these drugs work in the brain, this was the example that taught me this. This is a lady who had ALK rearranged non-small cell lung cancer. She had no disease in her body but then presented with numbness in her hand. And she had this 5-centimeter lesion in her brain. We offered her surgery and whole brain radiation therapy all of which she refused and so they put her on a targeted agent and you can see in three weeks that she's down to 3 centimeters and continue to shrink, all right. And so, if these drugs work in the brain, then what is the role of radiosurgery?
Well, with melanoma, the answer's relatively easy. The problem with the melanoma drugs is that there's not very many of them, even for the BRAF target. And their failure rate is actually about 40% to 60% at a median of 3 to 6 months. So as Dr. [inaudible 00:16:14] showed an example of, once the drug stops working, then it regrows in the brain and so it's pretty easy to decide you should just go ahead and give radiosurgery for these patients.
In lung cancer, however, the argument is very different. So, the difference is that particularly for EGFR...so for ALK mutated lung cancers...I think probably many of us are not seeing this anymore because the drugs are so effective in the brain. For EGFR mutations, that's perhaps a little bit different but there are many, many, many drugs coming out for these diseases. And so, when the first one doesn't work, the second one gets started. When the second one doesn't work, the third one gets started. And they all have some efficacy in the brain which is why they may never come to us. So, the argument from the medical oncology side is that not only are there many drugs available and so they can use one drug to take care of everything and not take on additional toxicity from our local therapies but the median progression free survival from each of these drugs in an additive fashion, all right, can be in the order of 12 months. So, it could be three years before you see these people from the time of their original brain metastases.
The flipside of that. So, the argument from our side, though, is exactly the same as with melanoma, which is that these lesions can regrow the minute the drugs stop. And so, when you finally get to the end and you've run out of options, then don't be looking at us, you know, to help you out because that's a lot of lesions we gotta treat. And in all honesty, there's no additional toxicity to radiation and targeted therapies together.
And so, to try and work out where we fit in with all of this, we did a multicentered study and the results of this have been validated in many centers now around the world, looking...comparing TKIs, so targeted therapy for lung cancer only versus TKI plus radiation up front at first diagnosis of brain metastasis, and what was really interesting...and so I have to admit this was a very unexpected finding but that even in the radiation group, even though they had more symptomatic, larger...and a larger size and a larger number of brain metastases, you can see that intracranial progression was actually better controlled after radiation than it was with TKI alone. And not only that, but that in fact translated to an improvement in overall survival. And so, in the graph here you can see that the purple line is radiosurgery plus TKI versus whole brain radiation therapy with TKI in the blue and then...and TKI alone. And obviously, we don't necessarily understand why there is an overall survival improvement but it may be...and these people, they live long enough that progression free survival is the determinant.
All right. And so, our current institutional practice is if the patient is eligible for radiosurgery, then first line treatment of new brain metastases should be concurrent TKI and radiosurgery. If the patient needs whole brain radiation therapy because that's a never treatment now, then they go ahead and get drug first and then hopefully that can be salvaged for fewer lesions down the line. Obviously, at failure, though, salvage options are again individualized. And so, there are some...few randomized prospective trials out there looking at first line TKIs and comparing TKI only to TKI and radiosurgery but the problem is most of those studies have become obsolete because of this new drug, osimertinib.
And so, what you can see here in this PET study on monkeys is that the penetration of erlotinib and gefitinib which was first generation TKIs is really very little in the brain and that this new drug, osimertinib, has incredible and irreversible penetration into the brain. And so, there is a new randomized study now looking at this. And so, this may again change how we view radiosurgery in this population.
All right. So, in conclusion, treatment of brain metastases has gotten more complicated. It's not just us first, then them anymore, all right. We have to work with them. I think it's important to play on the playground together. It is important to be part of the discussion of what the patient's systemic therapy is because together, you may be able to do better. It is important to weigh the efficacy and toxicity of what we have to offer versus what they have to offer. These people are living a long time. They're gonna need all of us, all right, just at different times. And we need to participate in the clinical trials and the data collection. And so, the Brainlab, you know, system registry, sorry, for data collection is something that I encourage you all to participate in because the larger numbers we have, the better we will be able to study this and say exactly what role do we play.
And so, I think together we will do better for our patients. Thank you.