Potential Therapeutic Options for Patients With Neurofibromatosis Type 1 With Plexiform Neurofibromas

Part 1 of the NF1-PN Roundtable

In this expert roundtable series, Angela Hirbe, MD, PhD, Washinton University in St. Louis, Missouri, leads a 3-part panel discussion on the management of patients with neurofibromatosis type 1 with plexiform neurofibromas (NF1-PN) with Julia Meade, MD, University of Pittsburgh, Pennsylvania, and Carlos Romo, MD, Johns Hopkins University, Baltimore, Maryland.

In the first part of this discussion, our experts give an overview of the potential therapeutic options for both adult and pediatric patients with NF1-PN.

Click to watch Part 2 of this discussion.

Transcript:

Angela Hirbe, MD, PhD: Welcome to Oncology Learning Network. My name is Angela Herbe and I'm an associate professor of medicine and pediatrics at Washington University in St. Louis where I direct the adult neurofibromatosis clinical program. I also run a research lab focused on biomarker development and therapeutic target identification in NF1. I'll be moderating today's discussion on NF1 with plexiform neurofibromas and I'm joined by 2 distinguished experts in the field. We’ll start off by having each of you introduce yourselves and tell us a little bit about your roles. We’ll start with Dr Carlos Romo.

Carlos Romo, MD: Hi Angie. Thank you for letting me introduce myself. I'm Carlos Romo. I am an adult neuro-oncologist at Johns Hopkins and I am also an attending physician in the Neurofibromatosis Center here in our program. And I also do clinical research as part of the Neurofibromatosis Therapeutic Acceleration Program or NTAP here at Hopkins.

Dr Hirbe: Excellent. And Dr Julia Meade.

Julia Meade, MD: Thank you for having me. I am a pediatric oncologist with a focus on children with neurofibromatosis type 1. I'm the director of our NF-oncology program here at the University of Pittsburgh School of Medicine.

Dr Hirbe: Excellent. Well welcome both of you and thank you everyone for joining us today. NF one is the most common cancer predisposition syndrome affecting about one in 2,500 individuals worldwide and up to 30% of patients with NF1 develop, which are benign tumors with a very high morbidity and a risk for malignant transformation. Up until April of 2020, there were no FDA approved systemic drugs to treat and therapy was really limited to surgery, which can be challenging given the large and invasive nature of these tumors. And we know that in surgical resection it's rarely possible to get the entire tumor out and we often have regrowth of these tumors even after debulking.

We're going to start today's discussion with a look at the potential therapeutic options for NF1 plexiform neurofibromas. So the first question I wanted us to chat about is what are the available treatments for pediatric patients with NF1 plexiform neurofibromas?

Dr Meade: I can start with that. So, obviously in 2020 we had approval of selumetinib, which was the first MEK inhibitor that was able to be used for children specifically with plexiform neurofibromas. We have used selumetinib prior to this for children with brain tumors or optic pathway tumors through a variety of clinical trials through the Children’s Oncology Group. But expanding into plexiform neurofibroma, that was a real landmark event with the SPRINT trial. Since then, we've also had the FDA approval of mirdametinib, which is now our second option to treat children who have symptomatic and inoperable plexiforms.

Dr Hirbe: Can you weigh in a little bit on the risk-benefit profile of each of those options?

Dr Meade: Absolutely. We use both of them here at Children's [Hospital in Pittsburgh] in our clinical practice. The overall response rate in terms of tumor shrinkage and amelioration of side effects seems to be pretty similar. We're seeing about a 40% reduction in the size of plexiform neurofibromas, and we do have a lot of patients who report subjective improvements in pain scores, also, just general wellness, improved growth, improved weight gain, for a lot of our patients. On the outcome side of things, I think either medication is really an excellent choice.

When it comes to side effect profiles, I also find that they perform relatively similarly, with rashes being the most significant and persistent side effect. And then also both of them carry a risk for a reversible decrease in the ejection function of the heart, which is monitored similarly across both medications, risk for ocular complications such as retinal vein occlusion, which is quite rare. And then the occasional GI distress, nausea, vomiting, which is pretty transient in both. I would say that it really comes down to nuance when we consider which medication might be a good first start when we see a new patient with a plexiform neurofibroma.

Dr Hirbe: That's good. Thank you. Dr. Romo, can you weigh in on the available treatments for adults with NF1-PN?

Dr Romo: Absolutely. Happy to talk about that. And I think first of all, I'd like to say something that's very important that just because a plexiform neurofibroma is present, it doesn't necessarily mean that you need to treat it. And in many cases, especially in the adult population that I see, they are there and they're not causing any symptoms, so you may not want to treat that patient, but you absolutely must monitor those tumors because of the known risk of potentially converting into this bad form of sarcoma called malignant peripheral nerve sheath tumor or MPNST. And one thing also to mention since I'm talking about MPNST, is that unfortunately none of the treatment options that we have available are known to prevent that cancerous transformation. So when I'm starting a patient on treatment, I make it clear that my goal is maybe to improve symptoms or to shrink the tumors because there's impending deficits that are going to happen if we don't do something about the growing tumors, but we're not doing it to prevent cancer and that I must continue to monitor for that potential cancerous transformation.

But having set those couple of disclosures, basically the treatment options are the same. We have small molecules that can help us with the improvement of symptoms and shrinkage of tumors and all of those are the MEK inhibitors. Only one is approved by the FDA for adults and that's mirdametinib, which was just approved earlier this year in 2025. And it's now available to use for adults and children with plexiform neurofibromas that are progressive or symptomatic or inoperable. However, we've been using other MEK inhibitors including selumetinib and trametinib and binimetinib in adults with neurofibromatosis type 1. And we've also used on occasion cabozantinib, which is another small molecule multikinase inhibitor that has shown some benefit in clinical studies, but it's also not approved for adults. And we try to use surgery when surgery is feasible. I think it's still considered by a lot of people the standard treatment option if the tumor is completely resectable and the surgery can be done with an approach that is nerve-sparing.

If you're thinking it's too complex, not all the tumor can come out and you'll probably damage nerves, you might want to start a MEK inhibitor, if you have the time to start a MEK inhibitor. We might talk about this, but MEK inhibitors take time to start giving their benefits. They don't start working right away. It's a lot of nuances on when and how to treat someone with NF1, but those are the treatment options that I would discuss with my patients.

Dr Hirbe: Sounds good. And do you see a similar thing to Dr Meade, in that you find a similar efficacy and safety profile across the MEK inhibitors?

Dr Romo: I do. I think so. If you read the studies, you'll find that there are some differences in the percentage of objective response rates, but also the populations in those studies are slightly different, so you have to take the results with a grain of salt — I don't like saying one achieved 40% or 42% and the other one closer to 70%, because the populations were different. Some of the tumors were progressing more so on one study than the other. For one study, more tumors were treated because of symptoms, not tumor growth, so the population is a little bit different. But in general, in practice, I think that they're pretty comparable in their side effects and their clinical and radiographic benefits.

Dr Hirbe: Good. And then to either one of you, when do you decide to use a MEK inhibitor? Dr Romo, you sort of alluded to being symptomatic plexiform neurofibromas in the adults. What is kind of your threshold for starting these medications?

Dr Romo: Yes, so for sure symptomatic is something that I would consider, but also I usually start it in people with impending problems. If I see someone who has a paraspinal neurofibroma, let's say in the cervical cord that is getting very close to the spinal cord itself, and every time I scan that patient, the tumor's a little bit bigger and bigger and bigger, I start thinking, do we need neurosurgery to be involved so that we can decompress the spinal cord, especially if there are already signs of myelopathy, for example. But if there are still no symptoms of myelopathy, maybe even in that patient, I could start a MEK inhibitor with the hope that it stalls tumor growth and potentially even shrinks it.

How bad do the symptoms need to be before I start treatment? I think that's patient dependent, and a conversation with the patient and having that discussion about the commitment of starting a MEK inhibitor, all the monitoring that is required, which is not minimal, unfortunately and also the potential side effects. And say, do you think that all these tests that all need to run, all these visits with ophthalmology, and for echocardiograms, and visits with me, are worth trying to relieve your symptoms, whatever they might be. And often cases, it’s no, I think my pain is very minimal and maybe we can try a gabapentinoid or something else to help with the pain. And in some cases, really, we need to start a MEK inhibitor and that's the discussion.

Dr Hirbe: Thank you. Dr Meade, do you have other things you want to add to that?

Dr Meade: In the pediatric population, we are probably more likely to also initiate a MEK inhibitor for cosmetic benefit. As you can imagine, children and adolescents, there's a lot of teasing and sadly some bad behavior that goes on, related to children who have plexiform neurofibroma specifically of the face, and that is a very large population that I treat. So, though one could argue that the patient doesn't have pain or dysfunction, just the fact that they are experiencing a lot of social stress and bullying at school related to their appearance, I think is a unique situation where in pediatrics we're also compelled to start a MEK inhibitor because we know that we can achieve some symmetry and some balance in the face that is going to help them in their social interactions.

Dr Hirbe: That's a really good point. We cannot underplay the psychosocial pressures that this patient population has to endure, for sure.
Is there something that makes a patient a good candidate for a MEK inhibitor?

Dr Meade: I can probably start with that one since we have a few more considerations in pediatrics. Prior to mirdametinib, in order to effectively take selumetinib, you had to be able to swallow pills or capsules, so that was a minimum point of entry. The FDA indication is that a child should be a minimum age of 2, which I think also typically goes with the ability to coordinate a swallow.

Nowadays with mirdametinib, we do have the ability to have a dissolvable and soluble tablet, which has not necessarily dropped the absolute age, but the functional age down to where I am treating children now who are just over 2 because we have the ability to deliver that medication effectively and safely.

Obviously, another important part of being a good candidate is having some of the social structures in place to seek consistent medical care, as Dr Romo pointed out, quarterly visits, ultrasounds and eye exams, blood work. We do need to have those support structures in place so patients can undergo that monitoring. Sometimes I will talk, similarly to Dr Romo, with people about risk-benefit of, is this achievable? We don't want to have you in a position where there are side effects that we can't capture.

Dr Hirbe: Sounds good. Dr. Romo, anything else you want to add to that?

Dr Romo: No, I agree completely. I think someone who is able, and— Unfortunately, one of the manifestations that can occur in NF1 is some learning difficulties, cognitive deficits. And so sometimes that's a little bit challenging to start a MEK inhibitor with someone who may not be able to provide us with information about what side effects they're having. I always try to ask if there's a support system with family members or friends that can help us as we're trying to schedule visits and make sure that we are in the know of any potential problems that are happening. But I agree with everything Dr Meade said.

Dr Hirbe: Sounds good. You've touched on this a little bit, but I think it would be nice just to do a quick compare and contrast. What are the main side effects that you worry about in a MEK inhibitor in the adult population, and what are your strategies for managing those? And then, the same question, but in the pediatric population.

Dr Romo: Sure. I think the side effects are very similar but not the same. I've seen both cardiac ejection fraction problems in both pediatric patients, I see a few pediatric patients, but also in adults. That rash happens in both, but the rash tends to be a little bit different — the rash in the peds, I'll let Dr Meade talk about a little bit more, but in young adolescents and adults, young adults, typically we see this acneiform rash, which is exactly what it sounds like: someone looking like they have acne and it affects any part of the body, but typically affects the face, chest, back, sometimes the arms as well. And I usually recommend either prophylactic treatment to try to avoid a more severe rash or, if the patient is not interested in prophylactic treatment, I have a very low threshold for starting topical treatment and even an oral tetracycline to help with the rash if necessary. I've talked with dermatologists about that, they also recommend in some cases a bleach bath, which sounds kind of scary, but they say it's very efficacious. You just put a little bit of bleach in your bathtub, fill it up, and soak for a few minutes, and that helps with the rash. But I use hydrocortisone cream for the face.

Tacrolimus is also something that I've used in the past to help with that, clindamycin ointment. And I typically prescribe ketoconazole shampoo if someone has a very scaly, itchy scalp, that can also help with that.

For the GI problems, I can start treatment depending on what the problem is, so I can start antinausea medication. I very rarely actually need to start that, but if someone is experiencing that, either I dose-reduce the medication, a little bit or start an antinausea medication. If it's diarrhea, it can help with Imodium for example. But that's again, a rare problem.

A lot of the side effects, and I have to say most people on a MEK inhibitor will develop a side effect. For example, someone alluded to the SPRINT trial before, and 99% of the patients in that study developed a side effect of some sort. However, the most common one was asymptomatic elevation of creatine kinase or CK or CPK. And that usually just requires monitoring but no actual intervention. I use it as both of a marker of whether the patient is taking the medication or not, because almost everyone develops CPK elevation, so if you're not taking your medication, chances are your CK will be normal. But I monitor that closely to make sure there's no kidney problem. There's a very small risk of rhabdomyolysis, but it's there, and I look for that too.

Dr Hirbe: Sounds good. Dr Meade, on the peds side?

Dr Meade: Yeah, on the peds side, definitely rash is our biggest culprit. And to Dr Romo's point, we have lots of ways that we treat these rashes. These are in children and adolescents, and they're very concerned about their appearance to begin with. I do a lot of prophylactic counseling about how bad the rash can get and the fact that we need to give this medication a longer time period than they would like to see efficacy while they will see side effects first. And so really convincing them ahead of time, your face may look like a hamburger, we can get through this, don't stop your medicine just because your acne is really bad for 2 months. I think that really helps set the stage and they can then accept that this side effect is bad but transient.

We partner really closely in pediatrics with dermatology, and every NF-oncology program has its ancillary service lines where you're working with closely with a dermatologist, an ophthalmologist, a cardiologist, and you really have to have a team in order to make your system scalable and work. Having a good helper to manage rashes is very helpful. We also do see a lot of paronychia, both of the fingers and toes, which we’ll partner with podiatry on the foot side, and again, dermatology if it's in the hands, in order to make sure that we are using either steroids or antibiotics to mitigate that.

Honestly, a lot of the side effects of MEK inhibitors are a nuisance side effect, is what I tell people. The reason you want to quit this medicine is because it's such a hassle with the side effects, not because something bad is really going to happen. I think managing those expectations are really important, especially from the get-go.

Dr Hirbe: Excellent. Thank you. I'll kind of briefly summarize this first portion. We do have finally systemic options for patients with neurofibromas. And currently we have 2 drugs that are FDA-approved in the pediatric setting, 1 drug that's FDA-approved in the adult setting. And these drugs seem to have similar efficacy, similar safety profiles, and managing the side effect profile is very important so that patients can see the benefit to these drugs.

Thank you for sharing your insights and thank you to the audience for watching. Please join us for part 2 of the discussion, where we'll explore the recently published data from the ReNeu trial.