Evaluating Treatment Response and Managing Toxicities in Pediatric Low-Grade Gliomas
Mohamed Shebl Abdelbaki, MD, St. Louis Children’s Hospital, Washington University of Medicine in St Louis, Missouri, addresses the practical challenges of monitoring response and managing toxicities with pediatric low-grade glioma (pLGG) therapy.
In the final installment of this video series, Dr Abdelbaki highlights the shift from contrast-based evaluation methods toward more accurate imaging criteria to better capture subtle treatment responses in these patients. He also reviews key adverse effects associated with targeted therapies for pLGG and explores emerging strategies to overcome resistance.
Transcript:
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.
