Chapters Transcript Video Low-Intensity Focused Ultrasound (LIFU) for Non-Small Cell Lung Cancer Brain Metastases Welcome to the Baptist Health Doc to Doc podcast, a conversation for physicians by physicians, providing insight on the latest in medical practice, research, technology and innovation in health care on the Doc to Doc podcast. Dear colleagues. I'd like to welcome you to another Miami Neuroscience Institute podcast. And I'm here today with Man Meet Aalia, who is Chief Scientific Officer, Chief of Medical Oncology, and Deputy Director of Miami Cancer Institute. He holds the endowed professor chair, the Fernandez Family Foundation, endowed chair in cancer research. I'm Michael mcdermott. I'm a neurosurgeon. I'm the Chief medical executive at Miami Neuroscience Institute. And today we're gonna be speaking about a prospective clinical trial on the use of low intensity focused ultrasound for non small cell lung cancer, brain metasis. Uh Doctor Alia, could you give us a little background on the prevalence of uh this kind of tumor, non small cell lung cancers, the gender distribution, previous treatment results and overall survival. It's a big topic, but you got the ball. Uh Thank you, Mike and so glad to be with you here today. So as you know, non small cell lung cancer is around 80% of all the lung cancer that we see in United States. It is one of the most common types of cancers. Over 200,000 patients are diagnosed every year in the United States. What we also do know that the most common stage in which non small cell lung cancer presents is stage four. That means the cancer has spread outside the lung, often can go into liver bones or brain. And we know whenever a cancer goes to the brain, it's not unfortunately good news. What we are excited about is that in the last decade or two, there has been tremendous progress made in stage four lung cancer where on an average people lived around 12 months or so, almost two decades back. And now people are living over two years and the five year survival has increased from 5% to 20 to 25%. Still brain metastases continues to be a significant clinical challenge for these patients. And we'll address that. But you had asked the question regarding gender specificity. Uh what we've been noticing in the last decade or so that there's an increasing incidence of lung cancer in women and particularly in women who are non smokers. And there was a nature publication in the last year or so, actually showcasing that pollution, just small particulate pollutants can actually lead to increased inflammation in the lung that can actually lead to non small cell lung cancer. And in particular type, there's an oncogenic driven lung cancer called EGFR or epidemic growth factor receptor kind of lung cancer where this leads to a particular increase in that. So, on one hand, we are seeing a great improvements in outcomes. But on the other hand, we are picking up new patterns of lung cancer, which may not have been either recognized or we're not there at that level. Yeah, that was my experience in my career in radio surgery over the last 30 years. In the last 15 years, I've noticed an increase in the number of young women in their forties and fifties who were never smokers, never exposed to second hand smoke. And I guess we don't really know whether it's the inorganic or the organic particular matter that's responsible for the inflammation. Now, a variety of uh treatments exist for patients with a small number of brain metastases when it's so called stage four. And that includes uh surgery, radio surgery, whole brain radiation therapy, which is used much less commonly. Now, um, you're involved as a principal investigator for a trial BT 012. Uh using low intensity focused ultrasound per to the administration of pembrolizumab. Can you tell us a little bit about the trial inclusion exclusion, et cetera? Oh, sure, absolutely. And you know, Mike, as you know, you've been one of the leaders in the radio surgery aspect of treating brain metastases per se. And so there has been significant interest developing medical therapies and then finding avenues to help medical therapies get to the brain. So, one of the challenges that exist for brain tumors of brain metastasis, which is not there for other metastasis is this issue of blood brain barrier, which is a lining around the brain that you know protects us from every time you have a blood infection, you may get a brain abscess. It essentially exists at the level of the endothelial cell and capillaries within the brain. Absolutely. So what this trial is trying to do is it's trying to use low frequency ultrasound to help disrupt the blood brain barrier to increase drug delivery, but also using the ultrasound to actually help in something we think of is in terms of immune priming. So what we do know is even for example, radio surgery, if you use it, it can help to increase the new epitope expression. So, in a way you can help immune prime these cancer cells to augment the response immunotherapy even further. So, what this trial is doing and you are integrally involved as one of the leading physicians at Miami Cancer Institute on this is that we deliver the focused ultrasound and then we use PLO zab. And at the second intent, we're going to use PLO Zum with a number of chemotherapies as a triplet combination to even enhance this further. And the hope is that the ultrasound can disrupt the blood brain barrier, but also use immune priming to augment the immunotherapy impact we can get from PBZ Aab. Now, some trials have shown puma may work well by itself but not to the degree to replace the local therapies that we use like radiosurgical. Yeah, it's interesting. You mentioned immune priming and that reminded me of this so called abscopal effect. Do you want to tell our colleagues about that effect? Oh, sure. So, you know, a obscur effect is something that we have been delving into for years. And uh Sylvia ferment has done a fair amount of work in this as well. And basically what it relates to if think if someone has a brain metastasis, they have three brain metastases from say even lung cancer. And as a neurosurgeon, you may go and deliver radiosurgery or some form of radiation, maybe focus radiation to the largest lesion and but you may not deliver it to the two lesions. But this combination of the radio surgery or radiation along with immunotherapy may help increase or augment the benefit you may see on the second or the third brain metastases where you have not delivered a local therapy. And there have been New England Journal of medicine publications and spine. Sometimes when you have radiated one portion of the spine, the second portion of the spine that you did not read will regress as well. Sometimes beyond what you would just think with uh immunotherapy. So I think we're in a tremendously exciting era of scientific exploration. We are being able to measure things which just makes it so exciting to come to work every day. Yeah. One of the studies we did with rapes ka, one of our uh medical student researchers was looking at the molecular profile of the primary tumor versus the brain metastasis. And we found that they were different. Is that true of other? Is it true in lung cancer? Is it true? I know it's true in Melanoma and renal cell. Can you tell us a bit about how that might affect the results of the trial? Yeah. So we use a term called subtype switching. So what we know is in breast cancer, for example, there are women who have hormone positive and her two positive disease. And sometimes we use therapies which is particularly directed against the her two with these targeted therapies and there is a loss of the gene expression. So what we find out is that brain metastases have a different level of expression than what is seen in the primary tumor. So you mentioned about PDL one expression, we do know there is almost like a 15% discordance between the PDL one expression in the brain compared to what we are seeing in lung cancer. And sometimes it may be present, one place will not be present the other place. So it's, it keeps the role of neurosurgeon important because you want to go and actually sample those not going to be out of a job any time soon. That's good. Now, um the preliminary work on low intensity focus ultrasound showed significant elevations of drug concentrations inside the metastasis that were operated on after the administration of that treatment. But what about the brain immediately adjacent to the margin metastasis where some, there can be some microscopic infiltration depending on the pathology type. More come with squamous cell and melanoma, for example, than adenocarcinoma. Um Do you think that's gonna be important that that um increased drug constipation immediately adjacent in terms of local tumor control? Yeah, I think it is, I mean, you know, again, we have two concepts, right? We have a blood brain barrier concept and then you have a brain tumor barrier concept as well. And you know, you as a physician scientist have, you know, is something we play a critical role and help us recognizing that. So what we do know is that we use trastuzumab, which is one of the monoclonal antibodies used against her two positive brain metastases from breast cancer. And Neil Liman and his group in Toronto actually did a radio labeled essay to basically show that the concentrations of the drug in the brain metastases increased several folds when they used this low frequency ultrasound. And as a result, we also saw tremendous clinical benefits in the patients. So that is one of the purview of this concept in this trial, but also a number of other trial concepts that we're working on. But I think this concept of helping just the microscopic infiltration is going to be critical and I would love to know your thoughts on it. Yeah, I think it's not such a problem with brain metasis per se as it is with other tumors, primary tumors like gliomas. But thanks for mentioning Neil Lipman. Shout out to him. He's a hometown boy in Toronto. Uh and he's done a lot of pioneering work in both low intensity focused ultra, as well as high intensity focused ultrasound. But can you give us a brief overview of your study? The BT 012? I understand it's a prospective multi center trial. Uh Its randomization is 2 to 1 with the control group. And you want, I mean, I've treated two of the patients with low intensity but for the audience, you can outline what the trial involves. First of all, I would like to acknowledge and thank you Mike for your leadership on this study, both locally and nationally with us because we need to work together. It takes a village to take care of these patients and you need the disciplines to work hand in hand, neurosurgery, radiation oncology and medical neuro oncology. So thanks for that. So the trial actually has got two aspects and we are in the first stage where we just have to show the safety of the procedure along with P and as you know, at Miami Cancer Institute and Miami Neurosciences Institute, we work collaboratively to treat two of the seven patients that have been treated so far on the trial. And so far we have seen that it's fairly safe and extremely well tolerated. And I would love to, you know, for you to share your experience. Now, the intent here is that can we build on the benefits that we would just get with immunotherapy or immunotherapy plus chemotherapy? So, what we do know from prior trials is that when you use immunotherapy alone to treat these patients, we see response rates which means shrinkage of the tumor by 50% or more in 30% of our patients. So what this trial is trying to see if we can, we double that and we have a base and design that means we can alter the number of patients we treat on the trial on the benefit they are getting. So the first aspect of trial where we are in right now is to showcase the safety of PLO zab along with Liu. And then when we reach that, the second aspect is going to be Liu plus pab plus chemotherapy. But then we will launch into which we think is the exciting component of the trial. More exciting component two is to one randomization with life fu plus medical therapy compared to just medical therapy alone, with the hope that the combination of life and the medical therapy will be twice as effective as just the medical therapy. So obviously, brain control is the issue here, not systemic control. Um And the radiographic responses, how are those gonna be analyzed to avoid bias? Yeah, sure. That's a great question. And we all struggle with it every day. And as you know, there has been an organized effort called Rhino and essentially what it is doing is looking at response rates specifically in the brain compared to resist, resist is something we use for the rest of the body. But as you know, in brain, we have specific challenges on top. So, Rhino is a group of some of the top researchers and you know, one of your colleagues from UCSF previously, you know, Suzanne Chang has been national international leader of that effort. And what we are trying to do is we are going to try to measure the response rates with immunotherapy plus LIU and we are building it in a manner that sometimes with immunotherapy, you may have an initial increase in the size of brain metastases rather than a decrease. But as long as the patients are doing well, you can continue to treat them. And then, but the ultimate hope is that the combination of Liu plus immunotherapy is going to be effective in helping shrink the tumors more. And so it's a it's a joint effort with the neurosurgeons and radiation oncologist. So let's say the Liu Plus drug proves it proves to be very effective compared to standard medical therapy. Um Are we gonna put life who head to head with radio surgery at any time. Do you think? You know? So I think, uh, we hope we get to that stage. We still believe radio surgery is one of the foundational ways to treat brain metastases. And there's a lot of data for that either alone but more interestingly in combination. So the hope is if we can use life to improve the response rates with medical therapy, the next iteration of trial actually will be a combination of radiosurgery, liu and then the medical therapies and hope that we can achieve in brain metastasis, what we have done things like lymphoma. So for example, you know, lymphoma is a great prototype of how initially we used to have one drug, then we went to two drugs and now we are using a combination of 4 to 5 drugs together. And here, as you know, brain, it's always multidisciplinary management. We do that for primary brain tumors. We do it for brain metastasis. So I still believe that that might be our best bet to help these people with long term survival. So, radiosurgery for induction and the liu and chemo for consolidation, so to speak in medical oncology terms. Um Now we know that breast cancer, lung cancer, melanoma, three of the most common tumor types. Is there a plan to investigate liu and chemo or immunotherapy with other types of cancers? Well, the intent is that, but we did start with lung cancers as you know, it's the most common cancer that goes to the brain, 50% of brain metastases that we see in clinic are from lung origin. The hope is to then go to breast cancer and melanoma. But ultimately, what we are recognizing is kidney cancer, for example, which is the most, fourth most common cause of brain metastasis is now being treated with a combination of immunotherapies as well. Very similarly to how we are treating uh non oncogenic tumors and lung cancer. So I think we will get to a state that we will have comb therapies based on how we treat diseases rather than the organs that diseases arise or these cancers arise from. Yeah, with the advent progression um and discovery using monoclonal antibodies for cancer. Uh Some of us were worried that the medical oncology group was going to try and treat brain metasis with chemo or immunotherapy alone. And I believe there are studies out there that looked at immunotherapy alone versus immunotherapy plus radio surgery and maybe you want to comment on those. Yeah. No, absolutely. So you know, we and others have done several studies whether there have been retrospective analysis or data collection from multiple other efforts. So I can particularly highlight a German effort of 23 centers across Germany where they treated 380 patients with brain metastases. And these were treated by the best choice based on physician recommendations. And so there was a group that was treated with immunotherapy alone, but they used the dual checkpoint inhibition of uh Ipilimumab and Nivolumab. And then a number of these patients were treated along with radiosurgery along with immunotherapy. And what we found out was that people who were being treated with radio surgery and immunotherapy had better outcomes in the ballpark of 24 months compared to 16 months for just with immunotherapy. Highlighting that local therapy is still extremely important in management of brain metastases and similar rapes Katoa, who you named before. When he and I were both at Cleveland Clinic, we had looked at a Cleveland Clinic experience of around 150 patients with lung cancer with brain metastases where we found out was that if radio surgery and immunotherapy was given concurrently or very close to each other, we got the highest number of complete responses. That means that brain metastases disappeared completely resulting not only in improved complete response rate but also increased in overall survival in those patients. So we have at Wam Cancer Institute but also at several leading academic centers around the country. Like to handle these patients in a multidisciplinary manner with a combinatorial effort of radiosurgery with targeted therapy or immunotherapy as needed for that particular patient. All right, let's reverse the tables. Um Ask me a question about recurrent brain metasis, lung or otherwise. How would I, do you have any questions for me as a neurosurgeon? No, absolutely. I mean, I think there are still some critical aspects of research or treatment that we, we need to find. So, one is we treat uh traditionally our patients with upfront brain metastases with radiosurgery, uh often with combination with immunotherapy or targeted therapy when these patients fail and they come to you at a referral center, maybe they were treated somewhere else. What's your approach to treat these patients? And what do you have in your toolbox? Yeah. Well, one of the first things of course is to determine treatment effect versus recurrent tumor, which is often difficult. Um, and we of course, review these at Radiosurgery conference every Wednesday morning. But, um, the other aspect is, you know, if the patient is symptomatic then and has a lot of edema associated with the metastasis and repeating the radio surgery. Although repeat, radio surgery has been shown to be effective and safe, uh in the setting of uh acute symptomatology and a lot of edema, repeating the radio surgery is only gonna make things worse. So, in those patients, we actually consider reoperation with brachytherapy. And I actually started doing brachytherapy in 1989. I'm afraid to say that was a long time ago, but I still do it. And uh I think it's, we've multiple publications on it for brain metasis. Brachytherapy failed in the prospective trials for malignant glioma and largely because of the associated toxicity. Now we're investigating, you know, C I 131 which is AAA shorter half life lower toxicity profile than iodine, which we used in the past um uh for glioma. So we'll, we'll see that's a more difficult nut to crack. But for recurrent brain metastases that are symptomatic, the reoperation and um brachytherapy is actually very effective. The edema resolves almost completely in 3 to 6 weeks. Uh One of the critical things we are talking about treatment effect versus recurrent tumor. We have to get a pathologic diagnosis, interoperate of viable tumor before we can do the brachytherapy implant. So, there's about a 20 30% incidence where we think it's recurrent tumor re operate. We find it's radiation necrosis and we stop there and take out the radiation damage. That's also an effective form of therapy for radiation necrosis is surgery. So, um anyway, I'd like to thank the audience for their um attention today that brings us to the end of this podcast on the use of low intensity focused ultrasound and uh um a clinical trial for non small cell lung cancer, brain metastases you using it in combination with pembrolizumab and physicians interested in uh referring patients for consideration of the trial should contact Julia Montoya at 7865947354. And thank you again. Thank you, Mike. To find out more about the topics covered on the Dock to Doc podcast. Please visit physician resources dot Baptist health.net. Created by
