Future Therapeutic Options in Neurofibromatosis Type 1 With Plexiform Neurofibromas

Part 3 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 final part of this discussion, our experts explore the future of research for NF1-PN.

Transcript:

Dr Hirbe: Welcome back to Oncology Learning Network. My name is Angie Hirbe, and I'm joined by Carlos Romo from Johns Hopkins University and Julia Mead from UPMC Children's Hospital of Pittsburgh. In this segment we are going to discuss the future of therapeutic options for NF1 plexiform neurofibromas. I wanted to hear from both of you, what is your opinion on the main unanswered questions in terms of the use of MEK inhibitors for NF1 plexiform neurofibromas?

Dr Meade: I can start with this one, since I feel like we get a lot of these questions from the parents of children. When you are thinking about putting your 2-year-old child on this medication, there is a long-term hope for the future for your child, that they will do well on this medicine, but also that fear. Some common questions that I get are, what are the long-term impacts of MEK inhibitor therapy? And I do have to be transparent with families that selumetinib was FDA-approved in 2020, this medication has been used in the clinical trial setting for probably a decade, decade and a half, and that we do not have 20-, 30-, 40-year long-term data in these medications. We are still learning how they may affect somebody as they become an older adult. I do try to be transparent about that.

We don't have data to suggest significant effects on bone health, puberty, as far as we can tell. There appears to be no effect on fertility, though we don't have a lot of long-term data from our children, again, who have been on this medication, to say that they've successfully had families as they have planned. I think that is something that in the next decade or two is going to become more understood: whether there is an impact long-term on reproductive potential. Those are some questions that I often get asked and for me, I have to just say that there's a bit of an unknown to some of those side effects.

Dr Hirbe: Sounds good. Dr Romo?

Dr Romo: Yes. I think another big question that will hopefully be answered soon in the next few years is a question about prevention, whether we can use MEK inhibition in very young kids who may be asymptomatic, but we're trying to prevent manifestations. One of the studies by the NF Clinical Trials Consortium, and by the team at the NIH, is going to explore that question specifically for plexiform neurofibromas in a study that is just opening now. Hopefully we'll get more answers to patients about whether we can use them prophylactically or not and whether that's beneficial or not.

Another question that I get asked often, and I alluded to this before, was the question about whether we're preventing one of the scariest NF1 complications, which is that cancerous transformation of these tumors. I think we don't know the answer for sure, but there have been case reports of people on a MEK inhibitor who develop MPNST [malignant peripheral nerve sheath tumor]. We think the answer is, it doesn't prevent cancer, but we don't know that for sure.

Another big question is how long do I need to take this treatment for? If I am past 15 or 16 years of age and I'm not going to grow anymore, could I stop my MEK inhibitor at that point? We don't know. And we think that these medications work as long as you're taking them. If, for whatever reason, you need to stop taking them, chances are that your tumors are going to be painful again or grow again. But those are all questions that we can't answer very accurately.

Also, we don't have good biomarkers to say you are someone who will likely do better or not. And I wish in the future we can have imaging, molecular, some form of biomarker that can help us say, yeah, I think your tumor is likely to benefit more from a MEK inhibitor or not. We don't understand why some people have that 60% reduction of their volume and some people have a 10% reduction. I think we want to understand that better so that we can triage patients better too.

Dr Hirbe: Those are all really good points. Do either of you use these medications either adjuvantly or neoadjuvantly?

Dr Romo: I don’t.

Dr Meade: I do, in the surgery setting. For example, for children with plexiform neurofibromas of the face, a lot of times we know that a surgery-only approach is not going to give you an effective cosmetic result, because the tumor tends to regrow and then you just have scar tissue on top of plexiform neurofibroma. But for patients who have a very good response to MEK inhibitors, and we find that there is an area of the tumor on the face that really just remains asymmetric, we will partner with our plastic surgeons to have that area cosmetically smoothed out and then continue on their MEK inhibitor. We haven't seen a substantial problem with wound-healing or other issues to the point that we stop them. So, we continue them on their MEK inhibitor through plastic surgery and those patients seem to have the most fantastic cosmetic effect.
In that setting, I will use it, but I don't use it in a cancer setting with MPNST or anything along those lines. I think that would best be explored in the setting of a clinical trial.

Dr Hirbe: And I was referring to neoadjuvant/adjuvant in the setting of a plexiform. I think those are interesting points and I think something that I hope to see formally evaluated in clinical trials at some point, is there efficacy in that?

Dr Meade: Agreed

Dr Hirbe: I think one other thing you mentioned, Dr Romo, that I wanted to circle back to, was this idea of what happens when you stop the medication. And I think in discussions with my pediatric partners here, I feel like that might be a little bit different in adults versus children. And I think that would also be something that would be interesting to formally look at, but I would love to hear insights from both of you.
In my adult practice, I don't tend to see kind of a rebound growth when patients stop a MEK inhibitor, but my gestalt is that that's different in the pediatric side. And so kind of interested in what each of you think on that.

Dr Romo: Dr Meade, do you want to start with this?

Dr Meade: Sure. I think we're working with small numbers and so it is patient dependent. I have definitely seen patients where when we stop their MEK inhibitor, they come back. Sometimes for growth, but mostly it's honestly side effect, or pain side effects. I have patients who say, oh, I didn't realize how much pain I was in until, I've been on this medicine for so long and when I come off of it, I feel so achy or stiff, I can't eat anymore. Especially for those who have plexiform in the abdomen. That really is the number one motivator. For the ones who have it on the face, growth is the number one motivator to restart their medication.

I would say in my practice, it's probably about 30% of people who go off —which I'm going to be honest with you, it’s not a lot of people who actually discontinue— 30% come back and restart.

Dr Hirbe: Interesting. I think that's good insight. Dr Romo, how about you?

Dr Romo: Yeah, I agree. I think it is a little bit of a different discussion, having a 6-year-old stop the medication versus a 60-year-old stop the medication. I think in most of my patients who needed treatment with a MEK inhibitor, the problem was not tumor growth but was symptomatic plexiform neurofibromas that just couldn't be operated.

And so typically when we stop the medication for whatever reason, I also don't see a growth curve that we hadn't seen before, to think that maybe MEK inhibitor was suppressing something that now is out and now causing tumor growth. But yes, symptoms are usually something that comes back soon after stopping the MEK inhibitor. not always. But I feel that people get pain again pretty soon after starting treatment, sometimes even a day or two after stopping treatment.

Dr Hirbe: Okay, thank you both of you for that. Can you each give me any insights on any other therapies with a target other than MEK that are being explored?

Dr Romo: Yeah, there is another study that will open, actually it's open now in some institutions, it's a multicenter study, also run through the NF Clinical Trials Consortium where we are exploring, still MEK inhibitor, but now in combination with cabozantinib. Again, I mentioned before that both of them have shown some promise as monotherapies, but there's data coming out from Dr Wade Clapp’s lab at Indiana University to suggest that there may be a synergistic effect of using the combination of both, and maybe by using smaller doses we can have a better side effect profile but get more benefit than we do with either one of them by themselves. So, the combination of selumetinib and cabozantinib is going to be explored in the near future in adults with NF1 and plexiform neurofibroma.

There's also a study by Healx Therapeutics, which is assessing what is usually prescribed as an antibiotic for urinary tract infections in Europe, not very commonly used here in the US. That will also open in the next few weeks, maybe some sites are already open for that study. We will be one of those sites, but we're not open yet for recruitment. But it is very exciting because it has a very nice side effect profile, completely different from the side effect profile of MEK inhibitors. And I'm excited to try that and see how it works and treating plexiform neurofibromas.

Dr Hirbe: That one is interesting and I think the preclinical data suggests that it's not working by hitting the MEK pathway, but I think its mechanism is unclear. So that's also an interesting question to delve into that maybe would open up the door for other therapeutic targets.

Dr Meade: In contrast, on the pediatric side, we generally lag behind the adults in our studies because of the regulations and special considerations that you have to take into account when you’re testing medication in children. So selumetinib, in that regard, was really an incredible experience because it was actually FDA-approved in children and not in adults. I assume that we are going to be following on the heels of the adult studies, and if there is signal on the adult side, then ultimately that will get recapitulated in pediatrics. So, there's nothing new or sexy going on in peds, that's unique to peds. I think we're all just excited to have 2 MEK inhibitors when 10 years ago we had nothing to help children with plexiform neurofibromas, so I think we're just kind of riding that high.

Dr Hirbe: Fair enough. Dr Romo, you brought up the combination study that is going to be opening soon with the selumetinib and cabozantinib and just wanted to hear some brief insights from both of you about combination therapy for plexiform neurofibromas

From my standpoint, I think about that, of course, all the time for the actual cancers: we’ve got to hit multiple pathways. But with combination therapy comes increased toxicity. So that always worries me a little more for a benign tumor, but would love to hear thoughts from both of you.

Dr Romo: I'm really excited about that study. I really am. Like I said, there's 2 strategies or 2 things that we thought about as we were designing this study. One, is that hopefully by using the smaller doses, we will get away with not too bad side effects. We'll see. Another thing to consider is that the 2 medications do have some overlapping side effects, so for example, hypertension can be driven by one or both, and so we'll be paying close attention to those kinds of side effects. But for example, the skin rash is something that we see more with MEK but not necessarily with cabozantinib. The study is designed so that we look at all the side effects, but to pay close attention to the overlap.

And the other thing is just the data suggesting that they may be synergistic. And actually the primary end point for that study is not the classic 20% volumetric reduction. We set the bar a little bit higher and said we are aiming for 30%. And so, we hope that they will be more beneficial than either of those 2 treatments, together.

But I agree it's not going to be an easy sell with patients. I think we have to explain really our rationale really well before people can start participating in this project. But I'm excited about the combination.

Dr Meade: Yeah, I think it's a hard lift. These medications are not cytotoxic or cytolytic. These aren't going to melt. And when we think about solid tumors, there is generally a place for reducing the volume with an end goal, especially in the cancer space, of getting to surgical or either you're taking it out or you're going to radiate it. We know that that's not an effective approach for plexiform neurofibroma, so I am think a little bit more skeptical in the sense that whether or not you get 20% shrinkage versus 30% shrinkage, I think what patients want is that it is completely gone. And I don't think that combination therapy probably of any medication is going to get us to that wish, at least with the technology we have today.

But I am always hopeful that there are other treatment options for people. We know MEK inhibitors don't work for everybody, alone in particular. So definitely excited to see how these results pan out.

Dr Hirbe: And to that point, it would be interesting to see if that combination works for those patients that didn't have a benefit to a MEK inhibitor. So maybe the combination will be beneficial to those patients.

I think, wrapping things up, we've all realized that it is very exciting that we have some systemic treatment options, but we still have many, many unanswered questions, as well as some very exciting clinical trials that are coming down the road. Hopefully, with even more research, there will be more clinical trials, and we can continue to improve things for our patients.

That concludes this discussion series. Thank you both for participating and thank you to the Oncology Learning Network for organizing this talk. Please check out www.oncnet.com to catch the rest of this discussion, as well as other updates on cancer care. Thank you.