Good afternoon, everybody. Thank you so much for joining us for today's educational session. My name is Brian Taylor. I'm a clinical pharmacist working for CSE Oncology. We're putting on today's activity. Just a few quick housekeeping notes before the faculty get started. If you have any questions that come up throughout the talk, please put those in the chat feature. We will collate those into a Q&A at the end. Pre and post tests will be done through a Survey Monkey link, which you will find in the resources tab on the left side of the screen. And also, if you're interested in seeing our faculty disclosures, they are available in the handout, which is also in the resources page. And with that, I'll hand it over to Dr. Belzberg, our activity chair. Thank you very much. Let's see if that works. OK, so first of all, we'd like to very much thank AstraZeneca for putting this on. We greatly appreciate that. We hope this will be educational to our group of neurosurgeons and others who are participating and listening to us. We hope that you send your questions to us so we can try to answer them for you and make this an interactive and good presentation for you. There are learning objectives. These are them. In general terms, we're going to learn about NF1. We're going to learn about what it is to understand how to manage a plexiform neurofibroma in particular, and what are some of the newer approaches being taken to that. I'm excited to introduce the faculty to you. You have two very, very good people who are going to be speaking to you. Dr. Andrea Gross, who's going to be talking to you about NF1 and Dr. Miriam Bornhart. Both are really top flight people for you. Dr. Gross comes to us from the National Cancer Institute. She works with Dr. Wiedermann, one of my heroes, who does phenomenal research. Dr. Gross's research is right up there with it. Dr. Bornhart, who also comes from the Washington area, but is at Children's National in Washington. She runs the clinic there and is doing that in conjunction also with one of the great leaders of NF, Dr. Roger Packer. Those are two excellent presenters. Unfortunately, the third one is me. I'll be coming up the rear in terms of just being a neurosurgeon here at Hopkins. I think you'll have a very good presentation in terms of us trying to balance where we're going with medical therapy versus where we're going with surgery for this. There is a pretest that we'd like you to take. We can give you a direction on how to get on that. It should be on the left side of the screen. I'm going to read the slides to you, but please go ahead and start taking that test. This is the SurveyMonkey. We're going on to it. So, what is your current level of confidence in using targeted therapy approaches for your patients with NF1? Not confident at all, which I'm sure most neurosurgeons would fit into. Somewhat confident, but still need some more information. Confident enough to use as part of a treatment team. And very confident. I already use them or plan to start. Which of the following is not a keystone diagnostic criterion for NF1? Again, which is not? Freckling in the axilla and inguinal regions? Presence of one or more plexiform neurofibromas? A second-degree relative with NF1 diagnosis? Or the presence of two or more leash nodules? And I'm out of control. When designing treatment strategies for NF1-associated plexiform neurofibromas, what are important considerations to make regarding traditional management modalities? Radiation is generally considered first line for plexiform management. Surgical debulking is especially efficacious in young patients with large plexiforms. Surgery is often clinically necessary, but pediatric patients with incomplete resection can have tumor regrowth. Neither modality is optimal. Surgery is often highly morbid, and radiation increases the risk for malignant transformation. And that wonderful E, both C and D. The emergence of targeted medical therapies is revolutionizing plexiform management paradigm in NF1. Which of the following statements about plexiform targeted therapies is true? A, no targeted therapies have been FDA-approved as yet for NF1-associated plexes. MEK inhibitors are the first class to show meaningful clinical activity. In phase 2 trials, pipperinib outperformed selumetinib for progressive plexiforms. And in the sprint trial, selumetinib achieved a 68% reduction, but no improvement in patient self-reported pain scores. And this is a presentation of a patient. CL, an 11-year-old female with NF1, presents to your clinic with a progressive plexiform on the left side of her neck. She reports discomfort despite gabapentin, and on exam you note a diminished range of motion. She underwent surgical debulking two years previously with a suboptimal or incomplete resection. MRI reveals approximately 25% growth over the past 16 months. No additional changes. Based on this presentation, what would you recommend? A, active surveillance, continue gabapentin. B, start the selumetinib. C, repeat surgical debulking followed by irradiation. Or finally, just active surveillance and increase the gabapentin. Next slide. So, with that, with your pretest, we're now going to pass you over to have your first presentation. Thank you very much. Hi, I'm Dr. Bornhuis. And as Dr. Belzberg mentioned, I'm the clinical director of the Gilbert Neurofibromatosis Institute here at Children's National Hospital in Washington, D.C. Sorry about that. I'm going to be talking about neurofibromatosis in general and give you a brief introduction as well to plexiform neurofibromas within neurofibromatosis type 1. So, neurofibromatosis type 1 is an autosomal dominant condition or syndrome. Half the time, it's something that's inherited from mom and dad. And half the time, it's spontaneous in a child. So, you can definitely see NF1 either in families or you can have a child come and be the first person to present with the clinical symptoms. It has variable expressivity. And what this means is that within NF1, there are a lot of different ways that children can present. Some children will have very, very mild signs and maybe just have skin signs. Other children will have a lot of different morbidity associated with it or a lot of different symptoms. The mutation is located on chromosome 17. And NF1 can really be diagnosed either through clinical criteria, genetic testing, or both. The NF1 presentation is very vast. It can include a lot of different areas of the body. The first thing we usually see would be the skin findings, which are the café au lait spots or freckling, which generally occurs under the armpits or in the groin area. You can also see cutaneous neurofibromas on the skin. And in GI, oftentimes, kids will complain of abdominal pain, vomiting. Constipation is not uncommon. But you can also see diarrhea sometimes with this. Within the kidneys, we can see renal artery stenosis. In the bone, you can have pseudoarthrosis. And that can be in pretty much any bone of the body, although the tibia are the most common and the fibula as well. Within the CNS, kids can present with seizures. They can have headaches, brain tumors. You can have blood vessel deficits. So moyamoya is more common in NF1. Learning disabilities and developmental delays are very common. About 80% of our patients will have some sort of a learning difficulty or developmental delay. And sometimes with that, you can also have decreased IQ. Macrocephaly is very common. So this is actually something that will oftentimes be referred to neurosurgery as a child with a macrocephalic head. And they're asked to be worked up for that. And then plexiform neurofibromas can also form in any of the peripheral nerves of the body. Within the eyes, you can sometimes have visual impairment. Optic pathway gliomas are seen in about 15% to 20% of kids with NF1. And then you can also present with Lisch nodules. And other things that we can see would include short stature, low weight, and then earlier delayed puberty. And there are some other cancers you can see with NF1. With the NF1 diagnostic criteria, there's a number of different things that you can see. But in order to make the diagnosis, you really just have to have two of these features. So the main diagnostic criteria listed here, café au lait spots and the skin-fold freckles, are the two that most often are seen. And so those are the ones that usually make the diagnosis. But you can also make a diagnosis based off of the presence of neurofibromas. So that would be either two solitary or one plexiform neurofibroma. If you see Lisch nodules, that can make the diagnosis. You have to have two or more Lisch nodules. Optic pathway gliomas is on the diagnostic criteria. Skeletal dysplasia, such as the bony pseudoarthrosis and sphenoid wing dysplasia. And then you can have affected first degree relative on the clinical diagnostic criteria. So this would be your mother or your father, for example, or potentially a sibling. What to expect and when. So with NF1, there's a timeline of what we expect and what we watch for. In the very young children, we'll start to see the café au lait spots. We can also see the orbital dysplasia, the tibial dysplasia. And that's when we actually start to see the plexiform neurofibromas. Now, for some kids, because of the location of plexiform neurofibromas, you may not diagnose it early in life. But most often they do start to form in between birth and infancy. As you progress through your childhood, we'll start to see new things pop up. The skin fold freckling usually doesn't come until early childhood. So that is one of those diagnostic criteria that oftentimes makes a diagnosis. But it's hard because kids don't necessarily present with a freckling until they're around three to five years of age. You'll also see on here that Leish nodules generally present a little bit later. Scoliosis is something that can come a little bit later as well. And then in adulthood, that's where we need to really start thinking about some of the cancers that can come with NF1, including NPNST, breast cancer, and high-grade gliomas. The diagnosis of NF1 can also be made with genetic testing or having genetic testing as a supplemental. So there are many types of NF1 gene alterations. And so that's a very, very large gene, and you can see just about anything. So each child with NF1 usually is unique, or there's very few children with the same alteration. Genetic testing can either be done through DNA, which is about 70% sensitive, or RNA. So this would be whole blood genetic testing. And on here, it says, what are we actually testing? So generally, to make the diagnosis of NF1, we would use a blood sample because we're looking to see if the child has an NF1 change in all of the cells of the body. But every once in a while, we will also ask for somatic or tumor testing, because there are some patients with NF1 who have a segmental or mosaic NF1, where there's only certain cells in the body that are affected. And the best way to make a diagnosis with that is to actually test those specific cells. So tumor tissue is something that we might ask for. And if we did, as neurosurgeons, oftentimes you'll be asked to save out a little piece, and then we would want to freeze it right away so we can send it for testing because that gives us the best results. Chromosomal microarray is also something that can be used for genetic testing, especially if you're looking for something called a micro deletion. I do just want to talk about the micro deletion briefly, because this is the one thing that we see with NF1 that is most or kids are most symptomatic with. So the micro deletion, basically, so within the micro deletion, you can see here that there's an NF1 gene. And around the NF1 gene, there are a lot of other different genes. So what the micro deletion is, is it's where you have not only this NF1 gene deleted out, but you have other genes around it deleted out as well. And the size of the micro deletion will sort of tell you which genes around it will be deleted out. And so for some of these patients who have, for example, the SUS-12 that's deleted out, their risk for NPNST is much higher because SUS-12 is something that can control cell growth and regulation, hence making it more likely for them to develop an NPNST. So with the micro deletions, oftentimes these children will have a very, very strong phenotype. And a lot of what you can see with the phenotype is included on the slide here. You can also actually see other phenotype, genotype correlations, and I listed some of them here. But the one that's sort of specific for this talk is this one right here, where you can have missense mutations in this particular region. And these patients are also more likely to get neurofibromas. So what is a plexiform neurofibroma? A plexiform neurofibroma is a low-grade nerve sheath tumor. They're almost exclusively found in patients with NF1, and they're found in about 40 to 60% of our patients. They have the most rapid growth in childhood in the early teens, and symptoms are largely secondary to mass effect and disfigurement from NF1. Symptoms are largely secondary to mass effect and disfigurement from the tumor itself. So your symptoms are going to be related closely to the location of the tumor. There is a risk for malignant transformation later in life, which you'll be hearing about later in this presentation. So how do these tumors form? Within the RASMAP kinase pathway, what will happen is within a cell, you get a signal that comes to the cell. And once the signal hits the cell, it goes through different pathways. So the RASMAP kinase pathway is a pathway that really is important for cell growth and regulation. So if the signal hits and it goes through the pathway, the cell is going to grow. NF1's job is to tell that signal you're not supposed to come through because the cell's not supposed to be growing, and it's actually supposed to stop that signal at the top so the cells don't grow. So if you have a cell that's mature and it's not supposed to be growing, NF1 is there to maintain that. But if NF1 is missing, when the signal comes, the signal is going to go through even when it's not supposed to. And all of a sudden, you're going to have cells growing when they're not supposed to be growing, and that's how you get a tumor that forms. The other thing I just want to mention that's important is that within NF1, when patients are born, they have one copy that's missing, so one copy that's altered, but the other copy is actually working fine. And so most kids with NF1 don't have problems throughout the body. But the areas where you have a second loss of the NF1, and now all of a sudden you don't have NF1 working at all, that's where you're going to have your tumors form, and that's where you're going to have your capillary spots show up in some of the symptoms you see with NF1. So it's that loss of function that causes the issues we see with NF1. This is just a slide to show some varieties of plexiform neurofibroma, and you'll get to see lots of pictures of this today. But again, plexiform neurofibromas can form just about anywhere on any nerve in the body. You can get abdominal. This one is one in the leg. This would be a peripheral neurofibroma, and this is in the neck. So CNS plexiform neurofibromas specifically, about 15% to 20% of patients with NF1 will have a spinal neurofibroma. The symptoms of the spinal neurofibromas are dependent on location and the extent of the cord involvement, and so close to 60% of patients will have some sort of symptom, but the most common symptom actually is pain. Only a minority of patients have neurological symptoms when they present, which is somewhere around one-third to one-half, but closer to that one-third side. The other thing that I think is interesting with paraspinal neurofibromas that we're learning more about is that oftentimes children who have paraspinal neurofibromas also have spinal curvature abnormalities or scoliosis, and so if you have a kid with NF1 and scoliosis, you should definitely think that they might have a plexiform neurofibroma along the spine. And then again, the neurological deficits are most common with cervical plexiform neurofibromas and those neurofibromas that they approximate each other at the same level and have compression of the cord. Surgery is still the standard of care for plexiform neurofibromas, and it's really best though for small and completely removable or resectable tumors. This is a paper that was recently released in 2017 looking at some of the complications in plexiform neurofibroma resection, and this is specific to spinal tumors, and they found actually a complication rate of about 32%, and there's a number of different things that can happen, so I think it is important to keep in mind that these tumors are really closely wrapped around the nerves and it is common to have complications from surgery. Another thing that comes up oftentimes is will the tumor progress or will the surgery make the tumor progress more after surgery? So there's two good papers that came out looking at this. One of them was in 1997, and there was a repeat one in 2013, and what they found in both of these papers is that after surgery, it's not uncommon for these tumors to progress or to grow again, and generally, it would be the younger kids or those that had less extensive resection that would come back, but what they found in 2013, which I think is really important, is that they looked at the rates of growth before surgery and after surgery, and they actually found that after surgery, the rate of growth did not change, so what this tells us is that, yes, the tumor may grow back, but the surgery does not trigger growth. It's just the tumor was growing before surgery, and it's going to keep growing after surgery. There are also new medical treatment options for plexiform neurofibromas, and you'll hear a lot more about this, but the reason I'm putting up this slide is that I just want to mention that plexiform neurofibromas are composed of a lot of different cells, so you have the tumor cell itself that has that abnormal signaling, but you also have immune cells and fibroblasts and other nerve-type cells that are involved in that tumor, and so what happens is as the tumor is growing, the immune cells try to respond, and then the tumor gets bigger, so when we're developing types of treatments, the treatments that we develop are those that will not only affect the tumor growth itself, like the MEK inhibitors and the tyrosine kinase inhibitors, but we also are looking at medications that can target the immune system, like peg interferon. So in conclusion, for my part, NF1 is an autosomal dominant condition that can be diagnosed clinically, molecularly, or a combination. Children with NF1 can present with a large spectrum of complications, and the phenotype of NF1 is very variable. Up to 60% of NF1 will have plexiform neurofibromas, and about 15 to 20% of those patients have spinal neurofibromas, and about 15 to 20% of those patients have spinal neurofibromas, treatment options for neurofibromas can include surgery and or medical targeted therapy, which you'll learn more about, and surgery can be very successful, especially in small, completely removable tumors, but it's also important to keep in mind that there is a risk of surgical complications and that quote-unquote tumor regrowth after surgery based on the natural history of the tumors. Great. Thank you, Dr. Bornhurst. So I'm happy to present today a talk about Employing Novelty in Plexiform Neurofibroma Management. My name is Dr. Andrea Gross. I work at the National Cancer Institute in the pediatric oncology branch, and I'm going to be focusing in primarily on one of the key manifestations of neurofibromatosis type 1 that Dr. Bornhurst mentioned, the plexiform neurofibromas. As she mentioned, these are histologically benign peripheral nerve sheath tumors that involve multiple nerve fascicles and branches. They are composed of Schwann cells, fibroblasts, and mast cells, and are also highly vascular. Again, they tend to develop at a young age, and may in fact be congenital, although we may not detect them until later depending on the location of the tumor. They have slow growth when compared to a malignant tumor, but they can become quite large and have very complex shape. The example here on the right is of a young boy with a left neck and shoulder plexiform neurofibroma. You can see here when he was three years old, it was very, very large and causing problems and obviously present on a photograph, but by the time he was five, it was quite disfiguring and had gotten large enough that it really impaired his ability to use the arm. This is actually not uncommon. Many of our patients with plexiform neurofibromas have symptoms from these tumors. They range from disfigurement, as in the case of this patient, to pain and other functional impairments, difficulty walking or using limbs, as well as life-threatening complications, for instance, when tumors compress vital structures such as the airway. In addition to the complications caused by these tumors themselves when they're in the benign form, there is a lifetime risk of approximately 10 to 15 percent of transformation of these tumors to the highly aggressive soft tissue sarcoma known as malignant peripheral nerve sheath tumor. The goal over the past 20 years has been to really look for targeted therapies that might help treat these tumors, because, as you can imagine, these highly interdigitated and complex tumors are often difficult, if not impossible, to fully surgically resect. One of the challenges in learning about the plexiform neurofibromas and determining whether a treatment has been successful or not for them has been measuring them. Again, using standard measurements like RESIST, using 1D or 2D measurements that we use for our malignant tumors, which works well for relatively fast-growing tumors, doesn't work as well for these slower-growing tumors that are really complex in shape. Therefore, over the course of the last decade, volumetric MRI analysis has really become the standard for evaluating the volume of plexiform neurofibromas in the setting of clinical trials in particular. The way this is done is an MRI is obtained of the tumor, and then at each level, the border between the tumor and the healthy tissue is marked, and an area is calculated, and then that area is added up to get a volume of the tumor. The reason I bring this up, again, is that this is considered the standard response criteria by which clinical trials have been evaluated for plexiform neurofibromas. Throughout the rest of the talk, I'll be referring to a partial response as a greater than 20 percent decrease in tumor volume, and progressive disease as a greater than 20 percent increase in tumor volume. What is the natural history of plexiform neurofibroma growth? As Dr. Bornhurst mentioned, they tend to grow most rapidly in young children. The graph on the right, you can see here, each dot represents the growth rate of an individual plexiform neurofibroma, and along the x-axis, you can see the age at the initial MRI for that plexiform. What this shows is that very few patients, once they get above 20 years old, have any growth above 20 percent per year, which is this gray bar here. Most of the patients that do have more than 20 percent per year growth are the younger age, and especially in the under 10 population. So this really points out the fact that these young patients, pediatric patients, have the rapidly growing tumors that may be most amenable to treatment. In addition, we found that though there are some tumors, especially in older adults, that do have slow shrinkage spontaneously without treatment, we did not observe in our population at the NCI, NF1 Natural History Study, any spontaneous shrinkage greater than 20 percent within a year. So again, this helps contrast with what we see or don't see in clinical trials. In addition, as Dr. Bornhurst mentioned, plexiform neurofibromas can cause significant morbidity, and in our NCI's NF1 Natural History Study, which was led by and has been led by Dr. Brigitte Wiedemann, we found that most of our patients, by the time we first met them at the median age of seven years old, already had some degree of plexiform neurofibroma-related symptoms. And again, this just emphasizes that children are a potentially good target audience for receiving treatment for these tumors, that waiting until adulthood may not be the best option for these particular tumors. The other thing we found in this population is that once a PN-related symptom developed, it was unlikely to resolve on its own. So if we do see resolution of the symptom, we can feel relatively confident that it was a treatment-related effect. I'm not going to spend too much time on this slide because Dr. Bornhurst touched on this already, but again, surgical resection has been the standard of care for plexiform neurofibromas for many years, and I know Dr. Belzberg will speak about this a little bit more, but it does have the risk of significant complications and significant risk for blood loss because they are highly vascular tumors. As Dr. Bornhurst mentioned, there is a risk in particular when there is incomplete resection, and young patients of having tumor regrowth. And again, it's not that surgery itself is impacting the tumor growth rate. It's just that these tumors were more likely to be growing prior to surgery and therefore are likely to continue to grow even after surgery. The other local control method that has been used for these tumors is radiation. This is generally not recommended. These patients have a tumor predisposition syndrome. They're already at risk for malignant transformation. And we know that any exposure to radiation does increase that risk. There have been small retrospective case series that have shown that radiotherapy can shrink these tumors. But again, this is not recommended because of the increased risk of malignant transformation. So how have we tried to target these tumors in NF1? As you can see here, again, this is similar to the diagram that Dr. Bornhurst showed a moment ago. But when you have neurofibromatosis, you are lacking the neurofibromin gene, which normally inactivates these pathways that lead to cell growth, proliferation, and survival. And so when you lose the neurofibromin gene, you lose the ability to downregulate or turn off these pathways, and you get excessive cell growth and proliferation and survival. The medications listed on the left here have all been used in clinical trials to try to target different parts of this pathway and the immune microenvironment, as Dr. Bornhurst mentioned. Unfortunately, though there have been, again, a multitude of clinical trials using these agents, you can see here on this Kaplan-Meier curve where the black line was a placebo arm from a TIPI-Farnab farnesyltransferase inhibitor trial back in the early 2000s. There hasn't been significant progress in enhancing progression-free survival in these tumors. The two agents, pegylated interferon and serolimus, did show some statistically significant improvement in progression-free survival. But one thing that's very important to note is that out of the 175 patients enrolled across all of the trials listed here, only two patients achieved a confirmed partial response. Remember, that's more than 20% volumetric shrinkage. And both of those were on the pegylated interferon alpha 2B. That's not a lot of patients having tumor shrinkage. And so, you know, one of the things that we've looked for moving forward is to try to find agents that would help with that problem. Since it's been such a challenge to find targeted agents for these tumors, preclinical models have become a really important aspect of the work. And here I'm showing an example of two different mouse models, one from the CLAC and one from the Ratner Lab, of plexiform neurofibromas. And what was really exciting is that these models were the first to demonstrate that targeted therapy, specifically the MEK inhibitor, in this case, the MEK inhibitors, myrtimetinib, actually showed tumor shrinkage in the mouse models. With this information, along with the targeted therapy and information about the mechanism of disease, a phase one trial of selumetinib was designed with the PI at the National Cancer Institute of Dr. Brigitte Wiedemann. The MEK inhibitor was taken twice daily on a continuous dosing schedule. This was for pediatric patients. And again, since this was a phase one trial, the primary objective was to define the maximum tolerated dose. This was, excitingly, the first treatment to show shrinkage of plexiform neurofibromas in NF1, as you can see here from the waterfall plot, where 17 of 24 patients achieved a partial response. Notably, this was achieved at 60% of the adult recommended dose for malignancies, which is important because our patients do not have a malignant indication, and they are taking the drug often for many years at a time. Excitingly, when these patients took the drug, they also had anecdotal improvement in some of their clinical symptoms, as you can see here from this young girl who had a large plexiform in her right buttock, or excuse me, her left buttock, that then shrunk pretty significantly with treatment. But, excuse me, and also at the same time, she had improvement in her ability to walk and less pain associated with that tumor. One thing that's important to note, you'll see here, the black dots is when she started treatment. The blue, the dot here, she actually had to be dose reduced for a side effect of the medication. And she did have tumor regrowth, which leads us to this, and other examples lead us to the conclusion that patients do require persistent dosing, especially in childhood, to maintain tumor response to MEK inhibitors. Overall, the MEK inhibitor was generally well tolerated, although there certainly are side effects, the most common of which are skin rashes, GI side effects like nausea and vomiting, as well as asymptomatic elevation in creatine kidneys. Though the phase one data was exciting, the FDA and the sponsor organizations agreed that it wasn't sufficient for drug approval because, again, these are not malignant tumors. And as you can see in the waterfall plot I showed a moment ago, the most tumor shrinkage we were getting was about 50%. So we are not making these tumors disappear. And so the FDA came back and said, we really need to demonstrate clinical benefit, which was the goal of our phase two sprint trial. And in that trial, our results were very similar. We dosed it using the maximum tolerated dose from the phase one trial, 25 milligram per meter squared twice daily. And the results showed a 68% response rate. But again, more excitingly, I think we actually were able to prospectively demonstrate evidence of clinical benefits. You can see here a young boy who has a large plexiform in his right neck that after three years on treatment got significantly smaller, caused less disfigurement. But what was more notable is that this tumor was actually growing quite rapidly and was imminently pushing on his airway. The family had actually been told he was likely to get a trach. And obviously with the tumor shrinkage, he had about 50% shrinkage of his tumor. It's doing quite well from that perspective. We also did a variety of patient reported outcome measures while on this trial to see if there was clinical improvement in addition to tumor shrinkage. This one looks at what we call the global impression of change. How much does a patient's tumor related problems change after a certain period of time? In this case, one year. And what you can see here, anything in blue indicates an improvement. And the only patients that reported even a small number of patients who reported a worsening in yellow here, those were all related to side effects from the drug. And the vast majority of patients had reported improvement in their tumor related symptoms. In addition, we looked at pain intensity from their plexiform neurofibromas. Pain is one of the most common symptoms that our patients with plexiform neurofibromas experience. And we were interested to look and see if we could demonstrate prospectively a decrease in pain. Using the NRS-11, which is the 0 to 10, 0 is no pain and 10 is the worst pain you can imagine in your life scale, we were able to demonstrate a decrease in pain. One thing I think is really interesting is that patients actually saw a statistically significant decrease in their pain as early as their pre-cycle three evaluation. So just after two months on treatment. So we do see this improvement in pain. If we're going to see it, tends to occur rather rapidly after onset of initiation of treatment. So we're going to go ahead and move on to the next slide. And this is a slide that I'm going to show you because I think it's really interesting. So as you probably noted, this was a single-arm study, not a placebo-controlled trial. So in order to demonstrate that we truly feel that the effect and the growth that we were seeing of the tumors and the shrinkage we were seeing was related to treatment of the natural history, we compared it to an age-matched cohort from our natural history study. You can see the age-matched cohort in blue and the treated cohort here in red. When you look at the Kaplan-Meier curves, of progression-free survival between those two groups, you can see that the median PFS for the natural history group was 1.3 years, whereas in the selumetinib group, the median had not yet been reached at the time of data cutoff. And at three years, there was 84% progression-free survival in the selumetinib arm compared with the 15% in the natural history arm. Similarly, when going back to that Kaplan-Meier curve I showed you before, Similarly, when going back to that Kaplan-Meier curve I showed you before, comparing to all the previous clinical trials, you can see that there's a clear separation of the selumetinib arm here in red compared with the other clinical trials. You will note that though there were 50 patients enrolled on the trial, there are only 21 patients included in this curve. That's because this curve only includes patients with progressive tumors that were known to be growing prior to study entry in order to match the eligibility criteria from all the previous trials. But again, there's a clear separation here. All of this data together led in April of 2020 to the Food and Drug Administration approving selumetinib for the treatment of pediatric patients with neurofibromatosis type 1 who have symptomatic inoperable plexiform neurofibromas. However, selumetinib is not the only active agent in these tumors. We know that other MEK inhibitors do have activity in NF1 plexiforms. In the NF1-106 study of mirtimetinib, they showed a 42% response rate with very similar toxicity profile. Similarly, trimetinib was also reported by Dr. McEwage et al. at ASCO in 2018 as having a 46% response rate and overall well-tolerated. And I'd like to thank Dr. Michael Fisher for these slides. Though MEK inhibitors were the first to show activity, a different class of receptor tyrosine kinase inhibitor, cabozantinib, or a different class of targeted therapy, a receptor tyrosine kinase inhibitor, which is cabozantinib, has also shown activity. Cabozantinib blocks MET, VEGFR2, CKIT, and RET, and has been shown to have significant effect on tumors, again, leading to plexiform neurofibroma shrinkage in about 42% of patients in an ongoing clinical trial. What's exciting here, going back to what I talked about with the preclinical models, is that this is also the only agent that shows shrinkage in one of the preclinical mouse models, which again shows that those mouse models have really helped us get a better sense of what's going to happen in our clinical trials and population. So where do we go from here with plexiform neurofibroma treatments? Well, one big question that still remains is, when is the optimal time to start treatment? Should we be treating only after patients become symptomatic, or should we be treating as soon as we know there is a plexiform neurofibroma? This is an active and ongoing question in the field. Similarly, what is the optimal duration of treatment? I showed you that when we had a patient who has dose reduction, when they are still a child, we tend to see tumor regrowth. So we know that patients need to be treated for some period of time to maintain response. But we also know that the tumors tend to plateau and stop growing on their own at some period in young adulthood. And so the question is, is there a timeframe when those tumors could stop being treated and will they regrow or will they continue? Again, this is something that's an active area of study. The best treatment duration and dose and schedule for targeted therapies is still being studied. These patients need to be on the medication for many years if they're going to be on it. So looking at whether an intermittent dosing schedule or some sort of dosing holidays could optimize the benefit while limiting toxicities. The UK and Dr. Roz Ferner's group is actively studying this. Similarly, looking at the long-term safety and tolerability. Overall, it was a tolerable treatment, but these patients are still being monitored for safety indications as they continue on drug. And then what impact do PN targeted therapies have on other NF1 manifestations? We know that MEK inhibitors have been effective for low grade gliomas. That has also been reported in NF1. But we are still studying their impact on cutaneous neurofibromas, cognitive function, and other NF1 manifestations. And with that, I'd like to hand it over to Dr. Balsberg. Thank you. We'll see if this works or not. Nope. Go ahead. Thank you very much. Those were really, as anticipated, great talks from our smart doctors, the oncology team and the pediatric neuro-oncology team. Now we're going to go over to the surgical side. So things will slow down in terms of some of the insights, but hopefully this will be intriguing for most of you as we start to think about some of these cases and how we would manage them. This slide just reminds us about schwannomatosis. That's one of the other NF things that we think about. So NF1, NF2, and don't forget the third one, schwannomatosis. And if you don't know about it, please learn about it. Next. So when we look at these slides, you can see here the variety of tumors that we deal with on the far left, the cutaneous neurofibromas, very typical. And then we go from the plexiform through the atypical and to the MPNST. And if you look at the histology down at the bottom, you can see a typical plexiform. Underneath the atypical or anubib, and we'll go through what that really means, is somewhere in between. Finally, the MPNST, a highly cellular and basically a sarcoma, for lack of a better term. We call them malignant peripheral nerve sheet tumors. Other people will simply call them sarcoma. It's certainly within the sarcoma family. Slide. The plexiforms occur again in about half the patients with NF1. They'll have a plexiform. They do grow rapidly, but usually it's when they're young. So as we've already seen that data. And then the unfortunate thing and the thing to always remember is somewhere between 10% and 15% of the patients who have a plexiform will go on to develop an MPNST in their lifetime. So that's always what you're thinking about at the back of your mind. Slide. So, again, it's a progression, and that's what we worry about. The patient who has that plexiform, we're always worrying that within that tumor, within the plexi, are they developing a more aggressive tumor? And I'll explain what an anubib is. That's the more modern term in Anubib, and is it going on to develop an NPNST? Should we be watching for it and how do we watch for it? Slide. This is how we watch for it. It's a busy slide, but the bottom line is what you're looking at is whole body MRI and added to the whole body MRI are some of the more modern techniques including diffusion coefficients, SUVs on different types of PET scans, and we're basically looking for a more aggressive tumor within a more benign tumor. Slide. So our big fear again is NPNST. That's what we're trying to avoid. That's where we're trying to spot it early and treat it aggressively. Slide. The real question is what is this Anubib? Anubib down at the bottom of that slide you can see is the atypical neurofibroma neoplasm of uncertain biologic potential or mouthful. What that really means is we're not sure what it is, and this was after a tremendous amount of work at the NIH with a number of our groups getting together and discussing it and trying to figure out are we going to call these atypical neurofibromas? Are they premalignant neurofibromas? What are they? Well, the bottom line is the pathologists are calling them Anubibs, but the surgeons and the oncologists and the doctors are saying it's basically a premalignant state. That's the way to think about it. Slide. So the risk factors that we have to worry about is is it an atypical neurofibroma? How do we spot that atypical neurofibroma, and what do we do with the atypical neurofibroma knowing that it's going to be a premalignant state? Slide. So for the atypical neurofibroma, do you resect it, and how do you resect it? Once it's been diagnosed and called an Anubib or an atypical neurofibroma, from a surgeon's point of view, that tumor needs to come out because it's premalignant. But the way that we're going to take that out is different from taking out an MPNST. The margin, which is the definition of surgical resection, the margin can be a marginal margin, meaning you only remove the tumor. We're not trying to take out the entire plexiform. We're not trying to take out all of the nerve associated with it. We just want that Anubib out. So you're hopefully not going to create any major deficit taking out just that part of the tumor and leaving the rest of the plexiform tumor. That's a distinct contradistinction, so to speak, of an MPNST where the margin is critical. And there you're going to want a safe margin around the tumor. If that means taking other structures and so on, you definitely want to have a full margin around an MPNST. So imaging has become critical. And as we manage these patients with NF, the critical factors are going to be whole body MRI is one of the most important things that's come into play. And if we look at whole body MRI, this is what it looks like. That's a typical whole body that we get with NF patients. It allows us to get a very good look at tumor burden through the body. It allows us to do volume metrics, which you already heard about, and follow the patients closely to see which tumors, if any, are growing and at what rate are they growing. So this has been a tremendous addition to the armamentarium for those people who look after NF patients. And if you're going to look after a bunch of NF patients, your radiology department needs to have this technology. Slide. Diffusion weighted imaging, otherwise known as the ADC or apparent diffusion coefficient, has also become a critical factor. What this looks at is the cellularity of the tumor. The lower the ADC number, not the higher, but the lower the number, the more cellular the tumor. And the more cellular the tumor, obviously, the more critical it becomes to differentiate that from a malignancy. So when we look at the diffusion coefficient, we want to see a high number, not a low number. The opposite of when you're looking at SUV on a PET scan, where the higher the number, the more likely malignant it is. Slide. This puts it all together. So now you're looking at a patient who's had it all. And this is what a typical patient in our setting would get if we need to look at tumors specifically. You're looking at a PET scan on the left and fused down below with the CT scan. And on the right, you're looking at whole body, but you're looking at ADC values on that same tumor, where we're trying to determine how cellular is the tumor, what's the likelihood that this is a malignancy. Slide. DTI, we're seeing pictures of, and in the neurosurgery literature, there's beautiful pictures of this in our publications. The question is, is it terribly useful? Well, this is basically showing you what people think are fascicular patterns. And perhaps it allows you to separate the anatomy, that if you're going to take the tumor, you're going to know where there's tumor versus where there are fascicles and how to reset the tumor. I don't quite think the technology is where it needs to be to truly make a difference in the surgery, but it's getting there. So we'll leave it at that. Slide. So what do we do with these tumors? That's a typical plexiform neurofibroma. And when you look at that, when you look at the histology, when you look at the gross, you realize this is multiple tumors stuck together. And from a surgeon's point of view, am I really going to reset only part of that? Am I going to get into that and be able to differentiate nerve that can be left alone and nerve that has to be taken? Obviously, that's a mess. And from a surgical point of view, you're either going in and debulking and taking out an awful lot of it, or you're not, but you're not going to individually separate those fascicles and start taking out individual tumors. That's simply not going to happen. Slide. As opposed to when we see a solitary neurofibroma, this is a beautiful example of a solitary neurofibroma, where you can open the nerve. And quite frankly, only one fascicle in this particular case was involved with neurofibroma. Remove that fascicle and nerve and you get a very good result. But that is obviously very different from the plexiform. Slide. So the question becomes, what are the indications for surgery? And these are our typical guidelines. Progressive neurological deficit, the growth where it's affecting an adjacent structure, growth of the tumor where we're worried about it growing quickly. The most common one is number four, pain. Sometimes we simply need the tissue diagnosis because we don't know whether this is atypical or even malignancy. And finally, where it is suspected to be malignant. And now we need a negative margin. We need a gross resection with a negative margin. Slide. One of the big questions that you're faced with is when do I biopsy? When is it that the radiologist says to me, well, I'm not so sure what this is. Maybe you should get a biopsy. And you have to decide, what are the risks versus the benefits? Now, there is risk to taking a biopsy. And I personally see patients who've had biopsies and end up with a nerve injury, a fairly severe nerve injury, simply from the biopsy. Or they'll do a biopsy, there'll be some bleeding in the tumor, and it makes it that much harder to reset the tumor cleanly later. So it's not a benign process, the biopsy itself. Having said that, you certainly want to know, or at least have a fairly good suspicion ahead of time if you're going to operate, whether or not a tumor is benign or malignant, because obviously the surgical approach will be different. Malignancy, unblocked resection, negative margin. That is the gold standard. That's what you need to achieve. So that biopsy may become very important. But again, it's not a benign procedure. What's always asked is false positive, false negative. This is the problem with false positive and false negative. If you look at the upper left, you see what looks like a normal neurofibroma. As you move to the right, you start to see a more cellular, slight atypia. If you come down to the left, you see a more aggressive, which would be an anubin or an atypical neurofibroma. And finally, if you go to the far right on the bottom, you're looking at an MPNST. All of that is on that one histological slide. So you can imagine the problem of trying to target that biopsy and get an accurate response with a needle biopsy when on a single histology slide, you see the entire gamut of pathology. So the biopsies will have positive and negative results in terms of a false positive and a false negative. It's unfortunate, but it is life. So let's look at how this gets managed. Let's go through a couple of cases. And I really want you to go through the case with me. I want you to manage it with me. What would you be doing when faced with this? What are you thinking? What are you guiding the family? And how are you interacting with your oncology team? So we will interact with our oncology team as well. So here's a one-year-old who presented with an upper respiratory tract infection. She has four cafe au lait spots, no other stigmata of NF1, a negative family history of NF1, no abdominal masses. They did the urines looking for VMA and HVA, but on that chest x-ray, there was a lesion. Slide. And that's what the lesion looks like on MRI. So you have a paraspinal lesion bilaterally. That is a classic plexiform neurofibroma. So this patient most likely has NF1. We can't make that firm diagnosis based thus far, but that patient probably has NF1, has a plexiform neurofibroma. And if you look at it, start asking yourself, could I resect that? Could I get a decent, fairly good resection such that that patient would be rid of the tumor? Slide. So we're faced with the question, and Harvey Cushing, by the way, was a good peripheral nerve surgeon. He used to do these as well. People think of him only as a brain tumor surgeon. He was a much more important peripheral nerve surgeon, just so you know. So the question is in this patient, should it be biopsied? Could it still be a neuroblastoma versus a neurofibroma? Is genetic testing going to be useful? And if it's a plexiform neurofibroma, given everything we've heard about the natural history of how this is going to grow, should we take it out now? Even if we cause a bit of a deficit, should the surgeon go in there and do an aggressive resection and prevent that patient from having to deal with a growing plexiform later in life and one that has, again, 10 to 15% chance of malignancy? So that is what we are struggling with as surgeons. And perhaps our oncology team can treat this with medications that will prevent the growth or even take away that tumor. But that's what we struggle with. Slide. So now let's look at another case and let's see how we manage the case and what should be done. So this is an early childhood. Did we skip one here? Sorry. Maybe not. Okay. Go. Slide. So in this person, we have surgery was attempted at eight years old to reduce the plexiform that you're looking at. Now at 10 years old, increasing discomfort requiring medications to control the pain. So this is a growing tumor. Slide please. Patient gets treated with gabapentin to help their pain, but things continue to grow here. And that's not a tumor that we think we're going to remove surgically. And certainly we're not going to remove it surgically and not cause a major deficit. So the question becomes, can this patient be treated with selumetinib? And more importantly, should they be treated with selumetinib? So I'm going to ask Dr. Gross, yay or nay, treat or not treat? I would go maybe. I don't, I, you know, I think the first thing you need to do is if a patient is having more pain that you need to rule out that there's been a malignant transformation or that the risk for malignant transformation. So I think if that gets evaluated and there is no sign of that malignant transformation, then yes, I think this could be a very good candidate for MEK inhibitor treatment. Okay. So the patient gets continued treatment with their MEK inhibitor and they actually do well in that terms. Slide. But unfortunately during that time, they do have an increasing mass that's a problem. And that increasing mass is seen biopsied and that turns out to be an MPNST. Slide. So there you see the histology, which is classic for MPNST. So now we've had the patient who's been treated this way and we're left with, now what do we do with this patient? What would be the next step? And I'll go to Dr. Gross again. What would be my next step? Yeah. So, you know, you kind of already showed it here, which is that you did an FTG PET scan to look for the PET avidity. So we know plexiform neurofibromas can be PET avid, but in general, they are low avidity compared in particular to either the atypical neurofibromas of uncertain biologic potential, those NBPs, which really does roll off the tongue, or the, or of course, MPNST. So usually our first thing to do would be to get a PET scan, as was done in this case. And you can see that that one nodule that was growing out of proportion to the remainder of the tumor, which it looks like had responded to the MEK inhibitor, which is what was concerning, is much hotter than the surrounding tumor. So we're going to treat this MPNST with aggressive surgery. We're going to do a nice big resection. We're going to get negative margins. Slide. I'm going to move along in the interest of time. Go to the next slide, please. And I'll ask about this one. Now we've done a nice resection, but is there a role again for medical treatment here, Dr. Gross? Sure. Yeah. So it depends if you have a full resection, there is definitely a discussion about whether or not neoadjuvant and adjuvant chemotherapy is appropriate in this setting. And I don't know if Dr. Bornhurst wants to jump in. The slide you kind of jumped through a second ago was talking about the only trial that's shown some efficacy, which is the combination of ifosfamide and doxorubicin, as well as ifosfamide and metoposide. But unfortunately, patients with NF1 related tumors, as opposed to sporadic tumors have slightly less response to those agents. In terms of if you are able to get the full resection, for that reason, there's again, some debate as to whether or not adjuvant chemotherapy is appropriate in that setting. If there's not a full resection, of course, radiation therapy and adjuvant chemotherapy are very much part of the treatment modalities. Okay. I'm going to get Dr. Bornhurst to comment on our next one. Next slide, please. So this is a young lady, three months of age, diagnosed with plexiform neurofibroma, gets treated for it, gets some cervical kyphosis surgery corrected and actually does very well over time. Comes back at age 16 with problems of growth of plexiform neurofibroma, which is asymptomatic. This is being followed radiographically. Slide, please. This is what it looks like. And you can see the tumor in the chest on both sides, a little bit worse on the left involving the brachial plexus, going down into the chest and up through the brachial plexus. Slide. And again, just another view. But in this view, you can see that within that plexiform tumor, left side of the chest, there's a separate tumor forming within, and that was very concerning. So further investigations are done on that tumor. Slide, please. It is hot on PET-CT, unfortunately. And that tumor now, we're starting to think, based on the PET-CT, we're starting to think about whole body view and ADC being low values, that that could be a malignancy. Slide. So with that, we decide to go ahead with a biopsy. Slide. That is diagnosed as an MPNST. So within the plexiform, in the chest, we have an MPNST. Slide. And now for the surgeons in the audience, what are we going to do with this tumor? Slide. Are we going to take it out? We're going to leave it. If we're going to take it out, how are we going to get it out? Again, you're looking at a solid MPNST within a plexiform, base of the brachial plexus, above the aorta, above the heart. Slide. So start thinking about, does it get treated with chemo before, chemo after, radiation before or after, and what would be the appropriate operative approach? So I'll ask Dr. Burhart to start. What do you think? Do we have to pre-treat with anything? Wait a minute. Yeah. Okay. So I'll just say really quickly that a lot of times the discussion as to whether or not we would start therapy first or go to surgery first depends on what the surgeons think. This is actually a case where I do think some pre-surgical adjuvant chemotherapy might be beneficial, particularly given the location. It also helps us to understand if the tumor will respond to chemotherapy or not, because if you get a little bit of response, then you can go to surgery, then you know that you could potentially do chemotherapy afterwards too. So I think that would have to be a discussion between the oncology team and the surgical team to make that decision. Okay. Fair enough. Slide. And what you're looking at is you're looking at the vertebral artery. I'm sorry, my pointer doesn't work, but you're looking at the vertebral going right through the malignancy. So her left vertebral artery goes right through the MPNST. So now we're faced with what are we going to do? And we decide on chemotherapy and we decide that we are going to knock off, we're going to go ahead of time, obliterate the vertebral artery, and then go in for surgery. Slide. So the patient's treated with four cycles of chemotherapy, radiation, or sorry, just the chemotherapy, the arterial coiling, then we do the resection, and then the patient gets followed up chemo. Slide. And this is what we were left with. That's just the plexiform on the bottom. The MPNST is gone. That's a very reasonable approach. She tolerated it all and did just fine. Slide. We're going to leave this one alone. So at this point, I'm going to not bother with any more cases because we're running out of time. We'll see if there's any pressing questions or comments from the audience. We have one minute. If not, I'm going to ask my two partners to comment simply. Is this still a surgical disease? Or is the medical management taking over and the surgeon's no longer needed in the treatment of a plexiform neurofibroma? Miriam, you're on. What do you think? Yeah, so I actually think that's a really good question. I do think this is still both. I think it's surgical and medical. And I think it really depends on the patient and the situation. And I have to say, since these new medications have come out and I've started to treat patients with both surgery and medications, that there's a new way to get good outcomes. And oftentimes, if you do both of them together, even the patients have better outcomes. So definitely not going away from surgery. I refer to surgery all the time. So we need you as surgeons to continue to help us out. But I think that the medical side of it is also more promising now than it ever was before. Bottom line, we are a team. It is a multidisciplinary team in the treatment of neurofibromatosis. Oncology, surgery together, we got to work as a team. I'd like to thank everybody very much. And I hope you've learned some things about both the non-operative and operative management of plexiform neurofibromas. Thank you.

management

plexiform neurofibromas

neurofibromatosis type 1

NF1

low-grade nerve sheath tumors

volumetric MRI analysis

targeted therapies

MEK inhibitors

surgical management