What Comes After Dabrafenib/Trametinib Intolerance in Pediatric Low-Grade Glioma?
Mohamed Shebl Abdelbaki, MD, Washington University St. Louis, Missouri, presents the case of a 9-year-old girl with unresectable BRAF V600E–mutant thalamic pilocytic astrocytoma who developed significant pyrexia syndrome and treatment intolerance while receiving dabrafenib plus trametinib.
Through this case-based discussion, Dr Abdelbaki reviews the available management options, including targeted therapy modification, chemotherapy, observation, and tovorafenib, and explains the factors that inform treatment selection in pediatric low-grade glioma.
Transcript:
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. I'm also the director of the clinical research office for the hematology, oncology, and bone marrow transplant division at [Washington University] as well. I'm really honored to be here, and what I would like to discuss with you is a question that I get so many times from patients and their families in addition to from different neuro-oncologists and oncologists around the country and around the world as well.
This question is regarding pediatric low-grade gliomas, which is the most common pediatric brain tumor, and we luckily have now several targeted therapies that are approved by the FDA for treating patients with newly diagnosed BRAF V600E-mutant pediatric low-grade gliomas using dabrafenib and trametinib, the combination of both, in addition to the FDA approval for tovorafenib for patients with recurrent, progressive pediatric low-grade gliomas. The terminologies have caused some confusion regarding which drugs would be more suitable to be used for the therapy for these patients and this is why I have a quick case that I would like to discuss with you. This will open up this conversation and make us think about what we would do in that case scenario.
The case that I have prepared for you today is regarding a 9-year-old girl who was diagnosed with a pilocytic astrocytoma, which is a WHO grade 1 tumor, in April 2024. She has a mass in the right thalamus and, as we all know, you typically cannot obtain a resection for thalamic mass given that this is an area that would cause significant morbidities if the neurosurgeons try to attempt a complete resection or even a partial resection and we typically get a biopsy performed in these cases. This brings an important point where the importance of the multidisciplinary neuro-oncology tumor boards, and the discussions between the neurosurgeons and the neuro-oncologists on the available therapies, since we have so many available therapies for pediatric low-grade gliomas it would be very relevant for us to share this information with our neurosurgeon so that they would not attempt complete resection in patients with presumed pediatric low-grade gliomas that may end up affecting their quality of life since these are patients whom we expect that they would have long-term survivorship.
For our patient, the biopsy was performed, and the diagnosis came back as a pilocytic astrocytoma, WHO grade 1, and most pilocytic astrocytoma do have a BRAF-fusion however this patient had a BRAF V600E mutation which happens in a small percentage, I believe between 6% and 9% of patients with pilocytic astrocytomas. As per discussions with the family, and making sure they're aware of the standard of care which is currently again has been FDA-approved for the combination of dabrafenib and trametinib in patients with pediatric low-grade gliomas who are newly diagnosed with BRAF V600E mutations. Our girl, CK, was started on this therapy however, she had pretty significant side effects which has been described for this combination– doesn't happen for all patients of course, but a portion of our patients may develop certain side effects. Her side effects were regarding pyrexia syndrome and there are ways for us to manage this in terms of antipyretics and starting steroids and considerate dose reductions and so on, however, unfortunately CK continued to suffer from significant pyrexia syndrome during the first 3 months of her therapy and she expressed that she does not want to continue this type of therapy anymore and her family was on board with that decision as well and they came to us inquiring about the treatment options that would be available at the time.
The questions that we have are questions that would come up to every one of us on how we would approach such a case. I've listed several, I think 6 options, and these options include: would you talk CK’s family and CK into continuing dabrafenib/trametinib despite the side effects that she's suffering from? Would you start a single agent with dabrafenib which had been used before in patients with BRAF V600E mutations before using the combination and has shown effectiveness? How about treating with trametinib single agent as well? Fourth option would be observing with serial imaging without any further intervention, and the fifth option would be starting the type 2 RAF inhibitor tovorafenib. Lastly, how about a chemotherapy option [with] carboplatin, vincristine, or vinblastine?
There are some instances where there is no right or wrong answer, as we know, however, in this case, in CK’s case, she's only started therapy 3 months ago and she had symptoms that led to the diagnosis of her tumor, we wouldn't expect that we would be stopping therapy within 3 months and not continue any therapy. Yes, we expect that there would be, in a certain proportion of our patients, some response from the dabrafenib/trametinib within the first 3 months and the problem is that when we stop therapy, there is a high likelihood of having profound re-growth and the tumor continuing to grow. In addition, we would prefer to see continued response which may happen up to 6 and 9 months after study therapy and therefore continuing observing with serial imaging if her symptoms are controlled and there's no progression is not a wrong answer, but this would not be without intervention– this would not be my first choice in this case.
The other choices regarding continuing the dabrafenib and trametinib, I would not continue this. We've tried multiple ways of addressing the pyrexia syndrome, as we've mentioned, and if this did not work and affecting her quality of life, I would not continue the dabrafenib/trametinib. If we're talking about a single-agent dabrafenib or trametinib that would not be a wrong decision either and we would not actually be expecting to see pyrexia syndrome as significant as we see with the combination.
Doing chemotherapy, I think is a reasonable option however, when the New England Journal of Medicine paper that was published by Dr Eric Buffet, I believe in 2023, has shown statistically significant improvement in the outcomes comparing trametinib to chemotherapy so I think that chemotherapy is a good option for CK but, it may not be my top choice in this case.
Last choice that we would like to discuss today is tovorafenib, which is a type 2 RAF inhibitor, and I think this would be a good option in CK’s case. It has been FDA-approved for recurrent progressive pediatric low grade-gliomas, there is a Nature paper published in 2024 by Dr Lindsey Kilburn that shows pretty good objective response rates and tolerability for tovorafenib so, I think this would be a good option to discuss with the family. Of course you have to discuss all the side effects, [we do not have] long-term data for side effects that may happen later on in life, but in this case, she did have significant side effects to the dabrafenib/trametinib combination. I think tovorafenib would be a good choice in this case.
If the family, the physician, after the discussions of the potential side effects and so on decide to start chemotherapy or single-agent dabrafenib or single-agent trametinib, that wouldn't be wrong choice, I would not favor as I mentioned, observation with serial imaging. However, I think using tovorafenib in CK’s case would be my top choice. I hope this is helpful and please do not hesitate to let me know if you have any questions, thank you.
