Advancing Care in Pediatric Neuro-Oncology

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Amy Smith, a Pediatric Neuro-Oncologist here at Cleveland Clinic. She is here today to discuss advances in pediatric neuro-oncology. So, welcome.

Amy Smith, MD: Thank you very much for having me.

Dale Shepard, MD, PhD: So, as we start, give us a little bit of an idea what you do here at Cleveland Clinic.

Amy Smith, MD: So, I recently joined the clinic just about four months ago. I am a pediatric-trained hematologist-oncologist and bone marrow transplant doc. And then I did specialized training in pediatric neuro-oncology several years ago, and have really spent my career taking care of children with brain and spinal cord tumors. And that includes everything from neonates to people in their 20s and early 30s.

Dale Shepard, MD, PhD: Okay. When we talk about pediatric brain tumors, what kind of tumors are we primarily thinking about?

Amy Smith, MD: So, different to adults, whereas in adults, half of what we see that occurs in the brain is a tumor from somewhere else in the body, but in pediatrics, we see brain tumors that are really primary tumors of the brain. And so low-grade gliomas as the most common tumors that we see. And even though that sounds benign, actually, they're not always benign, or at least not benign-behaving. And especially if they occur in the middle of the brain in the deep structures of the brain, often, you can't remove them with surgery, and so they often require treatment that can include different kinds of chemotherapy.

And now we're learning about all the biology of the tumors. And there actually has been a new drug approved just in 2024 that actually targets the pathway that we now know is disrupted in these kind of tumors. They affect the MAP kinase pathway. And there is a recent new FDA-approved drug called tovorafenib that was approved in 2024 for children with progressive, recurrent low-grade gliomas.

We also see medulloblastomas, which are malignant brain tumors and the most common malignant brain tumor that we see in childhood. And this is a tumor that, though it can occur in adulthood, really primarily is a childhood disease. Ependymoma is the third-most common tumor type. And again, can be seen across the ages of pediatrics and adults, but much more common in the pediatric group.

We do see high-grade gliomas, just like in the adult population. And for many years, people thought they were really the same disease. But through biology, we now know that these are actually very different diseases. And in fact, one of the things that we thought we would talk about today is the recent approval in August of 2025 of a new drug called dordaviprone, which has been approved for the use in pediatric and adult patients for patients who have diffuse midline gliomas, who have a specific mutation to the H3K27M gene. And from first-in-human to FDA approval took just about 10 years. And it's the first drug that's been approved for this disease, which really has been known as a uniformly fatal disease.

Dale Shepard, MD, PhD: So we'll dive in a little bit more about the drug and the sort of condition, but just so everybody understands, I'm going to double way back to ... you talked about benign tumors, but they can cause trouble. I guess, what are the biggest factors where a really non-cancer or benign ... is it really more just based on location and what it happens to press on? I treat desmoid tumors. They're not technically a cancer, but they can kill people. Is that sort of a similar concept here?

Amy Smith, MD: It is a similar concept. I think I don't really like the term benign, and probably you, as an oncologist, don't love that term either, because of this. If you have a benign tumor or a slow-growing tumor that's in an area that's easy to remove, and you don't need any other treatment, then that word maybe applies. But yeah, even if you have a tumor that can be completely removed in the brain, if you have to have brain surgery to have it removed, that in and of itself-

Dale Shepard, MD, PhD: Not so benign.

Amy Smith, MD: ... not so benign. But the clinical behavior of it may be very slow-growing. So I sort of like to think about it, and that's the way we refer to them, as low-grade or slow-growing versus high-grade malignant tumors. And you're right, their effect is very much related to location; everything, just like real estate.

Dale Shepard, MD, PhD: Location, location, location. When we think about tumors, whether they be low-grade benign or malignant, what percentage of patients are able to have them removed, versus needing medical therapies?

Amy Smith, MD: I think that's a difficult question to answer specifically that way. If you look at pediatric low-grade glioma, I think the survival for pediatric low-grade glioma is about 90%. I would say less than 50% of them can be completely resected, although I'm not sure that that's a great number, to be honest, to put out there. I think it's maybe a little different question, which would be, if you can get a complete resection in a pediatric low-grade glioma, your chance of survival and requiring additional treatment is extremely low. If you can't have a complete resection and your tumor continues to grow, there are therapeutic options, but you may have to require more than one treatment throughout your years of childhood. And these tumors are really important because they affect a child's development, both cognitive function, their motor development. A child may have seizures. If they occur in the brain stem, they can affect swallowing and talking.

So I think that, that really brings that type of a tumor into a totally different view. It's different than looking at a fully formed adult who may have some deficit. We're talking about these tumors, if you can't remove them, how does that impact the child's development throughout all of their life?

Dale Shepard, MD, PhD: You answered the question I should have asked. Let's go ahead and jump back into this dordaviprone and the condition it treats, and why has this tumor been difficult to treat in the past?

Amy Smith, MD: So the tumor is still very difficult to treat. These are tumors that occur in the midline portion of the brain. And so they're in the deep structures where they cannot be completely resected. Often, they're very infiltrative. So I always like to think about that more like weeds in a garden, so that even if you could take out what you can see, there are already tendrils of the tumor still left behind.

It also has a different biology to other gliomas in the brain that was not necessarily uncovered or discovered until several years ago, as we really launched into the genomic exploration of tumors, and really beginning to understand them at a deeper level. And so, that was important to identify first so that then we could understand the pathway, the driver that was causing the tumor growth, and then to look for something that could interrupt that growth. And so I think all of those components were necessary to get us to a place where we could identify a drug and then begin to test it and find something that could at least control the disease for a period of time.

Dale Shepard, MD, PhD: This particular drug works on a particular mutation. How prevalent is that mutation?

Amy Smith, MD: So in childhood, midline gliomas, the mutation is kind of synonymous with midline gliomas. And we see more midline gliomas in childhood than we do in the adult population.

Dale Shepard, MD, PhD: What is it really about this drug that makes it unique? Is it really just the ability to target that specific mutation that's in play?

Amy Smith, MD: It's a protease inhibitor. It's one of the first ones that I think has been approved. And so it uniquely impacts, when you have this mutation, how the tumor is driven. And so that's really the unique nature. And now there's another ... of course, the field will open up, looking at other permutations of that drug, or how to use other adjuvant immunotherapy approaches in conjunction with the drug to hopefully improve the response and disease control rates that we see.

Dale Shepard, MD, PhD: So, what kind of responses in disease control have we seen so far?

Amy Smith, MD: The approval came that patients had at least 10 months of disease control, which I know doesn't sound like much, but when you're talking about an aggressive disease that takes people's life often in under six months, if you can get the vast majority of them to have control for over 10 months, that's pretty good.

Dale Shepard, MD, PhD: From a side effect standpoint, has this been pretty well tolerated?

Amy Smith, MD: Yeah, actually, it is a pretty well tolerated drug. You can take it by mouth, so you don't have to be in the clinic getting IV infusions. And there are some skin and GI toxicities associated with it, but it is a relatively well tolerated drug.

Dale Shepard, MD, PhD: And so as we think about, like you say, months, sometimes, drug development's like watching youth soccer, everyone goes for the ball. What are the things that are necessary to make a better drug? Is it more response, better tolerability? What's going to be a win?

Amy Smith, MD: I think the win is always both, right? Because if you can give something that cures the tumor but it kills the person - We know this, everything that we do is a pro and con, weighing those balances out. Even though we're very excited that this drug is showing disease control in some responses, that's wonderful. But as I mentioned, it's not a home run. And so it's not a total win until we really either develop other isoforms of the drug that may be a bit more effective or may have less toxicity. But more likely, we're going to find adjuvant treatments that can go along with it that can treat the microenvironment around the tumor, help the body respond more effectively against the tumor, in addition to using the drug.

Dale Shepard, MD, PhD: From a drug development standpoint, was this different than a lot of other drugs we see? Was this like a big randomized phase III, or this was actually a series of non-randomized trials, is that right?

Amy Smith, MD: Exactly. And that's what unique about its approval, is that there were five open label studies going on that had similar eligibility criteria. So you had a midline glioma, you were having progressive disease, you'd had upfront treatment. So a relatively uniform population, though any time you're not having everybody in the same trial, there is some variability. But yeah, five open label trial, 50 patients, and saw a signal significant enough that got everybody's attention to be able to put that data together and say, "No, this is actually better than anything we've seen so far." And that's what led to the rapid approval.

Dale Shepard, MD, PhD: And I guess the question is, I mean, it is a big departure from how we normally think about drug approvals. For rare tumors, some pediatric tumors, do you think this is a new way that might pave the way for other therapies to be able to be approved?

Amy Smith, MD: I hope so, in many ways, because I have a little personal story that I think we all have experience, but running trials takes so many years. And my personal story is that I led a children's oncology group study for ependymoma. And from the time we presented the concept of that trial, my son was a baby, like nine weeks old. The study opened when he was five. It closed when he was in 10th grade, and we just published, and he's 21 years old. So when you look at how long ... that was a randomized phase III trial. Or if you look at the development of a drug that could take 20 years, or this one from first-in-human to start is 10, we're getting a little shorter. But yeah, I hope that this is going to be a pathway, because we've got to figure out effective and more efficient ways to evaluate drugs and combinations of drugs for patients.

Dale Shepard, MD, PhD: Yeah, because you figure that 20-year period was once you'd already done the preliminary work even to get to the phase III concept. So it's an impressive amount of time. So when we think about the tumors you see in your patients, what's the next tumor that you're really looking forward to a new therapy for? Is there anything that looks promising?

Amy Smith, MD: I'm always wanting something promising for all of my patients. I think the things that are exciting are, as I mentioned earlier, for patients with low-grade gliomas, the fact that we found the pathway ... the MAP kinase pathway is really disrupted in those diseases. And finding targeted agents for that disease, that is really exciting. And I think being able to treat those patients at an earlier time point, with those agents learning how to use them in the long-term and manage toxicities as children grow is going to be really important. And that is exciting.

The same has happened in the neurofibromatosis population in the last few years, as well, which we treat a lot in pediatric neuro-oncology, using those MAP kinase inhibitors. I think the populations for relapse and refractory medulloblastoma, ependymoma, high-grade glioma, finding new hopefully immunotherapeutic approaches, combination therapy between targeted and immunotherapy approaches will be, I hope, the next path forward that we find.

Dale Shepard, MD, PhD: Are you thinking that medical therapies are really going to drive more progress at this point instead of, say, new technologies in radiation or new technologies in surgery?

Amy Smith, MD: I think that all of the above are critically important, because as we have developed newer and newer technologies and surgery, our outcomes, our neurologic outcomes are better. Even delivery of some of these medical therapies, as we've done convection-enhanced delivery, is being utilized and studied for these diffuse midline gliomas. Those techniques are critically important in order to get drugs where they need to go. Also, radiation therapy, we all know, is very effective in many ways. And as we've developed more and more sophisticated techniques to deliver now proton therapy or other particle therapy, is critically important for curing tumors and preserving normal neurologic function. And so I really don't think that it's only ever going to be one pathway.

Dale Shepard, MD, PhD: Fantastic. That's a lot of good progress. So it looks like there's lots of exciting things happening in neuro-oncology in the pediatric setting. Appreciate you being with us today.

Amy Smith, MD: Thank you so much for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.