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Latest Advances in Pediatric Low-Grade Gliomas


Mohamed Shebl Abdelbaki, MD, St. Louis Children’s Hospital, Washington University of Medicine in St Louis, Missouri, gives a presentation on the latest advances in pediatric low-grade glioma (LGG). Dr Abdelbaki discusses frequency and outcomes of LGG in children, compares chemotherapy and targeted therapy options, and explains the criteria for evaluating responses in this space.

Transcript:

Good morning and good afternoon, everyone. My name is Mohamed Shebl Abdelbaki. I'm the director of the Pediatric Neuro-Oncology Program at Washington University School of Medicine in St. Louis, and I'm very excited to be here today to discuss with you the latest advances in pediatric low gliomas. These are my disclosures that may be relevant to our discussion today.

First, I will give you a quick background about low-grade gliomas in children, and then we're going to discuss the therapy options and the new advances in this field, in addition to a very important topic, which is the response evaluation criteria that may have evolved over the past few years.

I'll first start by stating how pediatric brain tumors now are the most common tumors or cancers in children up to 14 years of age, it has surpassed leukemia as you can clearly see here in this latest data, published in 2025. In general, I think— I had a hematology-oncology first-year fellow over this last weekend who thought that most patients with pediatric brain tumors do not survive. And the reason why, I think, is related to how the IPGs [intrinsic pontine glioma] or diffuse midline gliomas typically have very poor outcomes that many researchers around the world are working on improving these outcomes, and hopefully we're going to see improvement over the next 5 to 10 years. However, this is not the case for pediatric brain tumors. We're going to discuss the most common pediatric brain tumor, which is pediatric low-grade gliomas today, or pLGG as we're going to refer to it, and you're going to see how the outcomes look like. But looking at the outcomes for the most common malignant brain tumor, which is medullablastoma, you can see there are tumors that actually are very close to 100% survivorship in terms of WnT medulloblastoma, and survivorship is pretty good for those who have other subgroups in medullablastoma as well. And this is not the case for medullablastoma only, but we've made significant improvement in our ability to treat pediatric brain tumors over the last few years.

And I think we can owe this to the significant advances that we've made in terms of investigating the molecular landscape of pediatric brain tumors and identifying new subgroups in these tumors, which has led for the first time to the integration of the pathology and the molecular biology in the 2016 WHO classification for CNS [central nervous system] tumors. And this even evolved further into identifying 22 entities, new entities in the 2021 WHO. And if we start focusing on pediatric low-grade gliomas, we're going to see how now they typically happen in 6 families, 3 of which encompass pediatric low-grade gliomas. These gliomas are present in these 6 families and 3 of them encompass pediatric low-grade gliomas. And within these 3 families that we have here, there are 6 newer entities that have been identified and they are here in bold green.

pLGGs are the most common tumor in children and adolescents. The most common of them is pylocitic astrocytoma, and this number may be actually up to 20% now, it depends on the publications, but what we know is that pilocytic astrocytoma is the most common pediatric glioma and they happen in different locations around the brain and these are the most common locations: here in the diencephalon and the cerebral hemispheres, as well as the cerebellum. But the importance of this is that we would know that in more than 50% or 60% of the cases we’re not going to be able to achieve a complete resection. Surgery is the mainstay of therapy as we're going to discuss, complete resection would be the goal safely of course, but in around 50% or 60% of the cases in the diencephalon, optic pathway, brainstem, some areas in the cerebral hemispheres, spine, you're not going to be able to achieve a complete resection. And therefore, in most of our cases, we have to look for other modalities of therapy and this is what we're going to be talking about today. But it's very important for us to know that there are other options available, not only surgery for patients with pediatric low-grade gliomas.

And I like to talk about that figure on the left. As we can see, the overall survival for patients with pLGGs is not at 100%. I say that because we get this question all the time from families: pLGGs means my child has a benign tumor. Is that correct? Yes, it's accurate, but I always refer the families to the grades of brain tumor. You have a grade 1 and 2, so that's a low-grade tumor and a grade 3 or 4, that's a high-grade tumor. And I always state that grade 1 and 2 is slow growing, not aggressive. If you resect completely, that would most probably be the end of the story. But if you cannot resect completely, this is when we would consider it like a chronic disease and your child may be requiring therapy at one time point, stop therapy, different therapy at another time point and so on. I try to stay away from the word benign because some families think of benign, that means that it would never affect their child's survivorship and as we can see, it's not 100%. In order to stay away from confusing families, I like to explain it to them rather than just responding and saying this is a benign tumor.

And on the right, for any large comprehensive program, we work very closely with our neurosurgery colleagues in a multidisciplinary fashion along with so many other specialties. We typically see patients before they go to surgery or right after surgery. It's very important that everyone is on the same page, because the families think, how much is left, how big the tumor is? It's important to share these data with the family. A complete resection, yes, the chances of the tumor coming back is very small, but we have to manage this safely. A complete and maximal safe resection is the goal. If you don't have a complete resection, that's fine. There are many other options that we're going to discuss as we're going to talk about today. And if something is left back, it doesn't matter whether this is less than 1.5 cm or more than 1.5 cm, typically the size does not make a difference. This is very important so that our neurosurgeons would, with the families, we would talk comprehensively about our goals and our goal is for our child to have a safe resection that would allow us to make the diagnosis, would allow us to have a decent progression-free survival. But if that's not going to happen, we have many other options.

I think we tend to forget that we should not be only focusing on the overall survival and progression-free survival, especially in tumors that we are aware that these are long-term survivors and those patients will live for a long period of time: they will need to get married and have a driver's license and so on and so forth and be independent in life. Therefore, we have to make sure that we work with a multidisciplinary team, because even with a complete resection, these patients will have long-term effects. It depends on the location of the tumor and so on. You have to work with endocrinology, you have to work with ophthalmology, rehabilitation medicine, neurology, of course, and now with the targeted therapies as we're going to discuss, we have to work very closely with dermatology. So making sure that we treat these patients in a multidisciplinary fashion, explain the long-term sequelae of the therapies that we're using so that the families would not be missing other appointments once they learn about, oh, the tumor is stable, I'm not going to go to the ophthalmology visit. It's not that important to follow up with endocrinology. No, it's extremely important for us to be managing our patients with pLGGs comprehensively.

If we start discussing an important topic, which is how should we treat our patients? We talked about surgery being the mainstay of therapy, making sure that this is a maximal safe resection. I lead an international tumor board and we have cases from different parts of the world, and unfortunately for a case from a high-income country, the child walked in to the OR and came out with significant weakness, quadriparesis, because of the surgeon trying to achieve a maximum resection for a tumor that's supposed to be a low-grade glioma, turned out to be a paralytic astrocytoma. Which left the child with permanent weakness, for a tumor that could have been only biopsied and we could have treated with other modalities.

Chemotherapy, target therapy, we'll discuss. Radiation therapy is we typically leave as a last resort, but we have to still keep in mind for some of our patients who may be older and having progressive, rapid progressive visual decline or rapid progressive weakness, we have to keep that in mind for those patients and not exclude that possibility in our mind or our discussions.

Chemotherapy options, I think all of us are aware of what's out there. There are many chemotherapy options. I will discuss only the most common. Carboplatin-vincristine, as we see on the left, Joann Ater published this, the A9952 Children’s Oncology Group study that has shown that it has shown similar effects to TPCV, but the side effect profile is better with carboplatin-vincristine and that's why so many of our institutions consider this as the standard of care for patients with pLGGs, specifically for newly diagnosed BRAF fusion, as we are going to talk about. Vinblastine is another viable option. Eric Bouffet has spearheaded these efforts and the top graph is NF1, which will not be the focus of our conversations today. NF1 patients typically have better outcomes in terms of if they have pLGGs, but as we can see the progression-free survival for vinblastine is pretty similar to what we see with TPCV or carboplatin-vincristine, so definitely another excellent option to consider as first-line in the recurrent setting of course.

There are many benefits to the chemotherapy options. We know that there are no resistant mechanisms for them and if you use chemotherapy, you can use it across different histologies and molecular subgroups. We are very much aware of their side effect profiles, so very rarely there will be surprises regarding a new side effect that we're not aware of. All of our institutions have supportive care protocols for chemotherapy. But nothing's perfect in life, and with chemotherapy you have bone marrow suppression, the need for central line, you have to visit the emergency room at midnight if your child has a fever. Then there are hypersensitivity reactions, like up to 40% with carboplatin. Vincristine can cause neurological toxicities. Side effects to chemotherapy exists.

We are very fortunate that we've been treating patients with pediatric low-grade gliomas for a long period of time and they are commonly in locations that we’re able to resect and to gain tissue, and therefore many researchers around the world were able to identify how these tumors grow, It typically happens through a single driver alteration within the MAP kinase pathway, most commonly, and less commonly in the PI3 kinase pathway. And this is the RAS/RAF/MEK/ERK pathway, we're going to talk about this more. In rare cases, especially young adults where you may have more drivers, FGFR alterations may be associated with other drivers, but in general and most commonly, we're going to see 1 alteration that's driving the growth of these tumors.

We all hear about the KIAA1549-BRAF, in other terms and that's how we're going to refer to it afterwards, which is a BRAF fusion. So that's the most common alteration in patients with pLGG followed by BRAF V600E mutation in 15% to 20%, I would say. NF alterations, as well as other alterations along the MAP kinase pathway or the transmembrane receptors that we're going to refer to during this presentation. And as you can see, less commonly the PI3 kinase pathway.

The histologies, for someone who has not done or has not seen pediatric brain tumor patients before, the histologies may be a bit intimidating, but what I would urge you to do is look up the names because the names may be complicated, but what you have to think about is this a grade 1, is this a grade 2. Grade 1 and 2 are pLGGs as we discussed. If you look up something, and this is an anaplastic astrocytoma at grade 3, no, that's not pediatric low glioma. This would not apply to what we're discussing. And the BRAF fusions and mutations differ according to the type of histology. So that it would not be confusing: BRAF mutations can happen in high-grade gliomas as well. It’s not necessarily that you see a BRAF mutation, that means that this is definitely pediatric low-grade glioma. No, you may have this happen in higher-grade tumors, so if you do not know the nomenclature, please look it up. If it's a grade 1 or 2, that means it's a low-grade glioma.

How does it work? In general, and our focus will be the BRAF fusions and the BRAF V600E mutations, because these are the most common. When you have a BRAF V600E mutation, you're going to have an alteration that leads to the downstream phosphorylation and then the cell proliferation and survival.
If you have a BRAF fusion, it will be the dimerization of these 2 molecules that would lead to the downstream phosphorylation. This is very important that we're going to show this slide again, including the names of the drugs so that it would be very clear.

Identifying these BRAF alterations was very important in our ability to understand what are the drivers for pLGGs, how we're going to be treating them as you're going to see, but also allowed us to be able to identify which ones may be associated with poorer prognosis in terms of the progression-free survival. Which may be the case for patients with BRA V600E mutation, where they are more prone to have progression compared to those who have BRAF fusions. In addition to if you have less than a complete resection and BRAF V600E mutation, you may have lesser progression-free survival and if you have BRAF V600E mutation and CDKN2A deletions, this means that there is a higher chance that the tumor will come back or progress.

How would that be important? I think, it's informing the families making. We're not identifying the therapies for those patients yet, but making sure that we are following these patients closely if they have BRAF V600E mutation and CDKN2A deletions so that we would keep a close eye on these tumors. If you're going to space out the imaging for a patient with a completely resected BRAF fusion, I may think differently, if you're treating a patient with less than a complete resection, BRAF V600E mutation, and CDKN2A deletions. In addition to those with a V600E mutation and CDKN2A deletions, may be at risk for malignant transformation later on. It’s very important to inform the families and keep that in mind so that we would follow these patients closely.

How can we treat pLGGs using the knowledge that we were able to understand over the past few years?
On the left is the less common BRAF V600E mutation and since it's a mutation in that monomer, you can target using a type 1 RAF inhibitor, which is dabrafenib or vemurafenib as examples, or you can go downstream and target using a MEK inhibitor, which is trametinib, selumetinib, mirdametinib; these are some of the few available MEK inhibitors. Or you can use a combination, which now is FDA-approved in the newly diagnosed setting for BRAF V600E, using dabrafenib and trametinib, so a type 1 RAF inhibitor and a MEK inhibitor. Or you can use a type 2 RAF inhibitor, or as some would refer to it as a pan-RAF inhibitor. An example of this as tovorafenib, which is now FDA-approved in the recurrent progressive pLGG setting.

If we're talking about the most common, which is BRAF fusion, you can go downstream and stop the signaling pathway by treating with MEK inhibitor, or you can go upstream and target it using a type 2 RAF inhibitor, like tovorafenib, but you cannot use a type 1 RAF inhibitor, like dabrafenib or vemurafenib, in patients with BRAF fusion. This is extremely important and until 2 days ago from a neuro-oncologist, I received that question: if I have a patient with BRAF fusion, can I use the combination of the dabrafenib-trametinib? And this should not be the case. Why? Because it causes paradoxical activation. If you use a type 1 RAF inhibitor in the monomer, which is the BRAF V600E, this will stop the downstream phosphorylation, prevent the tumor from growing. But if you use it in patients with BRAF fusion, it will block 1 of the dimers, but it will not block the other one that will be active and lead to the downstream phosphorylation. Please, this is a huge take home message. Keep it in mind. You cannot use a type 1 RAF inhibitor in patients with BRAF fusion because it causes paradoxical activation. This is based on data from a clinical trial that was led by Matthias [Karajannis], and it has clearly shown that if you use a type 1 RAF inhibitor in patients with BRAF fusion, it causes this paradoxical activation.

If we start sharing with you how we were able to reach, so far, in terms of our knowledge on how to treat these patients and what are the responses that we typically see, I'll start by sharing data for a type 1 RAF inhibitor, dabrafenib in patients with BRAF V600E mutation. Darren Hargrave, it's nicely shown that objective response rates were up to 44%. You can see a very nice response rates here where typically, and this is the same case for all patients with on-target therapies, what we share with the families is that what don't typically see complete responses and what we typically see is partial responses, minor responses, stable disease, and pretty decent progression-free survival, that's similar to what we see with chemotherapies. That's why we focus on the clinical benefit rate, which includes stable disease, would be extremely important so that families would go into this journey understanding that stabilizing disease in terms of symptoms and radiographic appearance, would be extremely important and is a huge goal and we will be very happy to achieve it.

This is an example of a patient of mine who has a ganglioglioma and after only 8 weeks on dabrafenib, as you can see, a significant response. Again, the tumor is still there, but significant response radiographically and improvement in the symptoms as well. Dabrafenib-trametinib combination that we've discussed was compared to the trametinib single-agent and has shown that the outcomes in terms of the objective or overall response rates that includes partial responses as well as complete responses and sometimes it would include minor responses as well, has shown a benefit compared to trametinib monotherapy. This was tested further by Eric Bouffet in a huge study that was published in the New England Journal of Medicine. Dabrafenib-trametinib, up here, compared to chemotherapy, statistically significant improvement in the progression-free survival, not only this, but also in this side effect profile. This led to the FDA approval of this combination in patients with BRAF V600E mutation in the newly diagnosed setting. It's important to highlight that we have not tested against dabrafenib-trametinib against dabrafenib single agent. And that's why you should not be surprised if you see neuro-oncologists around the country who are treating with dabrafenib single-agent and they're seeing pretty good responses. It’s certainly an option, however, the FDA approval in the newly-diagnosed setting is for dabrafenib- trametinib in patients with pLGG and BRAF V600E mutations.
Moving down further, if we talk about MEK inhibitors, Jason Fangusaro has published excellent results for patients, on the PBTC consortium studies, using selumetinib in recurrent progressive pLGG, including NF1 patients, and Jason published the update in Neuro-Oncology this year. As we can see, the objective response rates and the clinical benefit rate is pretty impressive. A small percentage of these patients ended up progressing, as we can see here. And the median time to respond was 7.5 months. pretty close to what we're seeing, what we are going to be seeing with other MEK inhibitors or tovorafenib. I would stay away from comparing apples to oranges, in terms of which one is better, is it selumetinib, trametinib or other MEK inhibitors? We have not compared them in a clinical trial together and therefore I would take the data with a grain of salt in terms, of objective response rates here, overall response rate of 50% versus 55%. We cannot claim this is statistically significant because it has not been compared head to head. This is an example of a patient of mine on the left. The patient was treated with selumetinib and has spinal pilocytic [astrocytoma], as you can see. Significant improvement over a 12-month period on selumetinib with minimal side effects for this patient.

Selumetinib, we have data to show how effective it is as well in patients with optic pathway gliomas, which is very important to keep in mind that it led to improvement and stability in the visual acuity, led to improvement and stability in the visual fields. So, a very valid option for patients with deterioration in their vision. The question is, would you use it in a patient with rapidly declining vision. I think that different providers will think differently in that case. Some may use MEK inhibitors or other therapies as we're going to discuss in that case scenario. Others would prefer, based on the extent of disease, the age and so on to use radiation therapy in that setting. No right or wrong answer, but we have to remember how patients with optic pathway gliomas with deteriorating vision acuity or visual field defects can be improved or stabilized using MEK inhibitors like selumetinib.

These are examples of other MEK inhibitors. I will mention, in a couple of slides, about trametinib and mirdametinib. Mirdametinib has been FDA-approved as of late for patients with NF1 and symptomatic plexiform neurofibromas. It's an excellent option in patients with NF1 and plexiforms. But also, and I would like to thank Giles Robertson at St Jude's for sharing this slide with me. He presented these very interesting and impressive data for using mirdametinib in patients with recurrent/progressive pLGGs. As you can see, there's been effective in BRAF fusion, in FGFR alterations as well, with excellent response rates and a median time to respond that's pretty short. So again, an excellent option to consider for patients with BRAF fusions or your recurrent/progressive BRAF is under mutation as we said, you go downstream.

Trametinib is an option in patients with pLGG. There's a clinical trial, phase 2 study, that's testing it in recurrent/progressive pLGG and has enrolled as of January, 2022. I do not have the latest updates for the patients yet, and you can see there are similar numbers to what we've seen with selumetinib, as we're going to see as well with other agents where, if any complete responses, but mainly minor responses, partial responses and stable disease with a small number of patients with progressive disease. Trametinib is being tested in the recurrent progressive setting as well in patients in the Children’s Oncology Group study using vinblastine against trametinib and the results of which we're not aware of yet.

Tovorafenib is a type 2 RAF inhibitor that has been FDA-approved. This is a publication by Lindsay Kilburn in Nature Medicine a couple of years ago. The results of which the FIREFLY-1 study has led to the FDA approval for tovorafenib in the recurrent/progressive pLGG setting. Excellent responses as we can see in terms of the objective response rates as well as the clinical benefit rate as well. Interestingly, we've seen that some patients would have increase in the size of the tumors initially, that drops afterwards. Is that related to an immune response? This is currently being tested. We do not know yet, but how would I utilize this information for my patients? I make them aware of it before I start tovorafenib. And if I see a patient that has increased in the size of the tumor in the first 3 months without any clinical progression and I exclude the possibility that this is intratumoral bleed, which can happen with tovorafenib, I would continue the therapy for another 3 months with the hope, as you can see here in many of these patients, that tumor decreased in size afterwards. If you see continued progression, I think it would be completely fair to stop therapy and switch to a different therapy. But keep that in mind the potential of pseudoprogression with tovorafenib in the first 3 months and continue if you do not have any evidence of clinical progression, and if you exclude the possibility that this is related to intratumoral bleed.

The response rates based on the updated analysis that was released by the company shows objective response rates that are pretty similar to what we've discussed before: fifty-some percent. A small number of patients actually progressed. The median time to respond is pretty short at 5.5 months and a median duration of responses around 18 months, which is really impressive.

And this is an example of a patient of mine with ganglioglioma and BRAF V600E mutation. The patient was initially treated with dabrafenib and had pretty good responses. However, I had to stop around the 2-year mark because of side effects, then had rebound regrowth. So we started tovorafenib and as we can see, improvement in the size of the tumor as well as the clinical symptoms improved as well for this patient.

Tovorafenib, the visual outcomes has been published as well in 2024 and similar to selumetinib. It’s a viable option to discuss and consider for patients who have optic pathway gliomas and declining vision or in terms of the visual acuity or the visual field defects. And similar to what the data that we've seen for selumetinib, we've seen stability in the vision, improvement in the vision as well as a small number of patients who continued to have worsening with their vision. So, we have to keep that in mind when treating our patients who have declining vision and optic pathway gliomas.

This is a case example of another patient of mine who was 10 years old and had a pilocytic with BRAF fusion that involved optic pathway. She had this since she was pretty young and was treated with carboplatin-vincristine at one point, had clinical radiographic progression. Then treated with avastin-irinotecan and then had stability, then had radiographic and symptomatic progression. Started therapy on tovorafenib and again, one of the goals is not to have improvement in the size of the tumor. Stability is a goal, and we were able to achieve stability from a radiographic standpoint as well as a visual symptomatology standpoint.

These are the clinical trials that we've discussed briefly. That is comparing chemotherapy and targeted therapies in the BRAF fusion setting, because we do not know which one is better. We have FDA approval for BRAF V600E mutation, but we do not know yet: is it chemotherapy that's better, is it targeted therapy that's better? We do not know. That’s why we have these clinical trials that we've discussed. I apologize, I mentioned that the Children’s Oncology Group study is comparing trametinib to vinblastine, but it's comparing selumetinib alone versus selumetinib and vinblastine.

How would you treat patients with pLGG? If you have a complete resection of your pLGG, either this is a BRAF fusion or BRAF V600E mutation, what you have to do, is just observe and there's a very small chance the tumor will come back. Again, if you have complete resection that's not possible: a biopsy or some debulking. It depends. If you have a newly diagnosed pLGG with BRAF fusion, as we said, we offer 1 of the 2 clinical trials that's that are currently available, which is the Children’s Oncology Group study comparing selumetinib to carboplatin-vincristine or the FIREFLY-2 study, that's comparing to tovorafenib to carboplatin-vincristine or vinblastine. And we do not know the right or wrong answer yet, regarding which one is better. If the patient does not want to be enrolled on a clinical trial, they have to be aware that the standard of care is to treat with chemotherapy. Again, we discussed the chemotherapy options, carboplatin-vincristine, or vinblastine.

If there are some instances where some patients, we’re seeing more and more of this and we're seeing providers around the country treating patients in the newly diagnosed setting pLGG with BRAF fusion using a targetted therapy option. I think this can be done after making sure that the family's aware that chemotherapy is the standard of care, we do not know the long-term side effects of the targeted therapy options, and we may be surprised of a side effect that we are not aware of and therefore the families have to be aware that it's not because this is an oral drug that we're comparing to chemotherapy, that means it's better. No, the standard of care is chemotherapy, but in some instances, some providers may start targeted therapy in the newly diagnosed setting of a pLGG with a BRAF fusion. And we're seeing this happen around the country and we have to be aware that people are utilizing this option. In the newly diagnosed setting of a pLGG and BRAF V600E mutation, the FDA approval is for dabrafenib-trametinib. I think most of us are using the dabrafenib trametinib in that setting, I've mentioned some are using dabrafenib single-agent, but I think it's very clear that dabrafenib trametinib is the FDA approved option.

How about if you have recurrent/progressive BRAF fusion? It depends on what you have used initially, depends on if you stopped, let's say, and the patient had tolerated therapy or did not tolerate therapy, the patient was subjected to targeted therapy initially or subjected to chemotherapy initially. There's an FDA approval for tovorafenib in the recurrent/progressive setting. There are several clinical trial options in that setting. What I typically state is the data for tovorafenib, the FDA approval for tovorafenib. I mention the other clinical trial settings. It depends, if that patient had been treated with chemotherapy initially, I think it's completely fair to start tovorafenib in that setting. If that patient had been treated with, let's say, selumetinib initially and had excellent responses, then stopped therapy and had rebound regrowth, which happened in the first 6 months. I think it would be fair to restart selumetinib. Do not eliminate the possibility of starting what you had started initially, if the patient had tolerated it and had shown good responses with it. I think that's still an option in the recurrent/progressive setting, regardless of whether this is BRAF fusion or BRAF V600E mutation. As we're going to discuss, you may stop dabrafenib-trametinib and then you have rebound growth and therefore it will be totally fair to restart that same therapy again. If the patient tolerated it well, I think it's definitely an option. But in the recurrent progressive setting, we have an FDA-approved drug, tovorafenib. We may have FDA-approved drugs in the future, so we have to be aware of what's available and we have to be aware of how the patient responded initially and the side effect profile that we've seen with the medications that we've treated with initially.

We’re going to move on to the last part of the conversation, which is the side effects and the evaluation criteria. We used to evaluate the response with these tumors using the RANO High-Grade Glioma (RANO-HGG) criteria, which typically takes into account the contrast uptake as we can see here, which we came to understand that the contrast uptake may not be the best way for us to assess the responses in patients with pLGG in addition to the newer criteria, which is the RANO Low-Grade Glioma (RANO-LGG) and the RAPNO Low Grade Glioma (RAPNO-LGG) criteria takes into account the minor responses as well. Why wouldn't the contrast uptake be a good option for us to assess the response in pLGG? We have to rely on the T2 imaging, T2-FLAIR imaging. Of course we look at the contrast, but this is how I assess this response. This is an example of a patient of mine, you can see a brainstem low-grade glioma. This is the contrast uptake. It's not taking up the whole tumor, which is one reason why we cannot surely assess the size of the tumor based on the contrast, because the contrast may not occupy the whole tumor. But 3 or 4 months later, you can see if you assess the response with the contrast, you would say this is a complete response, that the tumor completely went away. But this is not actually accurate. And you can see at the same time point the tumor is still there. A message to every one of us and to our neuroradiologist, we have to assess the response using the T2-FLAIR and T2 imaging. In addition to the fact that in the patients that we follow without intervention, we sometimes see the contrast go up and down on its own without intervention, and that's the other reason why we should not be assessing the response based on the contrast uptake.

The challenges to target therapy — we talked about challenges to chemotherapy, again, nothing is perfect. We don't know the long-term effects, an extremely important point to highlight to the families. We do not know when to stop the drug. There are different resistant pathways. And, the rebound regrowth. And I think these two points are connected, which is, we typically stop therapy at 2 years. Is that based on our knowledge that 18 month is better than 24, is better than 36? We have no ide. We had to stop clinical trials at 2 years and that's how long we're using these therapies for. But you can see the median time to respond is actually short. Should we use them for a shorter period of time? We do not know. How about using it for a longer period of time? I think that's completely fair. We have this conversation with the families at the beginning, that we're going to continue therapy as long as your child is tolerating therapy and as long as we're seeing stability of the disease. One thing that we have to be aware of is that we typically see the responses at the beginning, first 6 to 12 months, but we're not going to see responses as much in the second year or the third year. Stability of the disease is a great goal and that should not be the reason saying, oh, we have to stop this therapy because we haven't seen any shrinkage for the past 6 months. In addition to, if we stop therapy, we have a high likelihood of having rebound regrowth as we're going to be discussing in a couple of slides.

What are the typical side effects? We see rashes, nail changes, cardiac function being affected, CPK elevation, maybe retinal toxicities, and some specific side effects that we've seen with tovorafenib, like the hair color change, the suppression of the growth velocity that has just been updated in the insert for the drug by the FDA. This is a patient of mine who started tovorafenib at the 97th percentile. Every visit we would discuss the potential of that this drug is clearly causing suppression of growth velocity and the family wanted to continue and we decided to stop here. You can see a significant drop in the growth velocity. You measure the suppression of growth velocity by looking at the height, and how much was the patient growing in the year prior to the study and on therapy.  Clearly the patient was growing only by 1 cm over that period of time.

We also know that tovorafenib causes suppression of growth velocity, but also does not cause premature closure of the growth plate and that we typically see improvement or catch-up growth or growth recovery after stopping therapy. This is an example of a patient of mine who stopped when they were at the seventh percentile and had significant growth within a very short period of time, I think only 3 to 6 months after stopping therapy and achieved this growth recovery. These data has been presented by Cassie Kline at ASCO in 2025, where 80% of the patients actually ended up catching up growth. 91% of the patients had growth recovery. This will be published soon, and the numbers may be changing, however, it's very important to keep that in mind when discussing tovorafenib as an option with the families. We always share the reasons for what we think is happening, that this is a pan-RAF inhibitor and therefore effects B- and C- and ARAF. And for CRAF specifically, since tovorafenib inhibits CRAF, this causes an impaired chondrocyte maturation, and then the reduced bone growth. But again, we do not know of any data that notes that there will be premature closure of the growth plate.

Rebound regrowth, we've talked about, it happens in many and most of our patients on targeted therapies. There are data as well for tovorafenib and that has been presented at SNO, but the number of months where the patients had stopped therapy has been very small, so we cannot make strong conclusions regarding it. But it's important to mention this to the families, that if we sign up to a targeted therapy option, we will probably have to stay on it for a long period of time because there's a high likelihood if we stop that, we're going to see rebound regrowth.

Lastly, the resistant pathways that may emerge. This is the work of Angela Waanders, when she was at CHOP, she’s currently at Lurie Children's, using trametinib-resistant cell lines. You can see increased phosphorylated ERK and pS6, which is a surrogate marker to the PI3 kinase pathway and increased expression along the PI3 kinase pathway in those tumors who were resistant to trametinib. If you combine inhibition of the PI3 kinase pathway and the MAP kinase pathway, you're going to see that the tumors are not growing. However, they have overlapping toxicities, and that's why looking at the combinations of the drugs that may produce an effect reducing either trametinib or everolimus. We're testing this in a clinical trial through the Pediatric Neuro-Oncology Consortium that I co-chair with my colleagues and friends, Lindsay Kilburn at Children's National and Angela at Laurie. And this is open, as we said, through the Pediatric Neuro-Oncology Consortium in several institutions around the country.

We’ve enrolled 27 patients so far. We started by the continuous dosing schedule and now we're testing the intermittent dosing schedule. This is a phase 1 study with a phase 2 expansion. We're still in the phase 1 phase, so I'm not encouraging anyone to be using the doses that we are using in the study because we're still in the dose-finding phase and we have not determined a recommended phase 2 dose yet.

This is an example of a patient of ours who's been heavily pretreated with FGFR alteration and as we can see, had significant improvement in the tumor and improvement in the vision as well.

Thank you for your attention and I hope that you have benefited from this presentation. I would like to summarize that there are so many options for patients with pLGG. If this is not resectable, we have to make sure that the families and our surgeons are aware of the many treatment options that are present under. Therefore, we have to aim for a maximal safe resection for our patients. Targeted therapies are now the standard of care in terms of dabrafenib-trametinib in the patients with newly diagnosed pLGG and BRAF V600E mutation. Chemotherapy is the standard of care for those newly diagnosed patients with pLGG and BRAF fusion. Many options exist in the recurrent progressive setting, however, tovorafenib has been FDA-approved in that setting.

Thank you so much for your attention and I hope to see some of you soon. Thank you.

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