Mirdametinib for Adult and Pediatric Patients With Neurofibromatosis Type 1 With Plexiform Neurofibromas

Part 2 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 second part of this discussion, our experts discuss data from the phase 2b ReNeu trial, evaluating mirdametinib among adult and pediatric patients with NF1-PN.

Click to watch Part 3 of this discussion.

Transcript:

Angela Hirbe, MD, PhD: Welcome back to Oncology Learning Network. My name is Angie Hirbe and I'm joined by Carlos Romo from Johns Hopkins University and Julia Meade from UPMC Children's Hospital of Pittsburgh.

In this segment, we are discussing the data from the phase 2b ReNeu trial, evaluating mirdametinib in adults and children with symptomatic neurofibromatosis type 1-associated plexiform neurofibroma. Mirdametinib is an orally bioavailable, highly selective, non-ATP competitive, allosteric MEK1/2 inhibitor with an IC50 of about 1 nanomolar against human MEK1. And this medication recently was approved by the FDA for adult and pediatric patients ages 2 and older with NF1 who have symptomatic plexiform neurofibromas, not amenable to complete resection.

Would one of you start off by discussing the inclusion criteria and the general trial design?

Dr Romo: Sure, I can take a stab at that. As you mentioned Dr Hirbe, this was a phase 2b study and the intervention was the use of mirdametinib in people, who had to have neurofibromatosis type 1 as per the criteria by the NIH, and they also had to have a plexiform neurofibroma at least, and usually that plexiform neurofibroma needed to be inoperable, symptomatic, or progressive to be able to join this study.

And there were other parameters, of course: patients should not be pregnant, female patients, and willing to be on oral, highly effective contraceptives, they needed to have basic bone marrow function, the typical things that we see for inclusion in a clinical trial. And also, be willing to have MRIs and tolerate MRIs, so that they could be monitored, because one of the primary end points was an imaging end points, so being able to tolerate MRIs was part of the inclusion criteria for that study.

It was done as an open-label study, not blinded and there was no control arm. Between 2019 and 2021, I believe, they recruited all patients and the data was just published last year, and that helped with the approval of this medication by the FDA for both adults and children because the study included 2 cohorts: one was a pediatric cohort, of kids ages 2 through 17, and an adult cohort of 58 patients that were 18 and older.

Dr Hirbe: Excellent. Let's move on and summarize some of the results. Specifically, we can talk about the response rate seen in pediatric and adult patients as well as what was seen in terms of patient-reported outcomes. Dr Meade, if you want to start with the peds cohort and then we can switch over to Dr Romo talking about the adult cohort.

Dr Meade: Yeah, this was a really exciting study. We were fortunate at the University of Pittsburgh to be a recruiting site, and so had several patients who are still on the ReNeu study. In total we had 56 children across the United States participate, that's about a reasonable number for a phase 2 study. And the overall response rate in terms of imaging was about 40% to 50%. We had some patients have a durable or prolonged tumor-based response. And again, this is all based upon the MRI findings, not so much the patient-reported outcomes.

One of the things that I really liked about the ReNeu study though is that they really built in patient-reported outcomes and specifically pain scores in their results. And they were able to demonstrate that there was a significant reduction in pain with extension in the use of mirdametinib over time. Which I think is really important because obviously though we would like everybody's tumor to shrink, more important than a tumor getting smaller on an MRI is, does the patient feel better? Are they functioning better, especially for children, are they now able to do things that they were no longer able to do? Are they using less prescription or over-the-counter pain medication? And it seems to be that the general trend with longer-term exposure to mirdametinib is yes, for a good majority of those patients.

Dr Hirbe: Excellent. Dr Romo, how about on the adult side.

Dr Romo: Yeah, in the adult side, as I've mentioned before, one of the end points was radiographic end point, meaning what they were trying to observe was a 20% volumetric reduction or more in the target plexiform neurofibroma that they were treating. And what they found is that 41% of the adults, meaning 24 of the adults that were enrolled in this study, actually achieved that confirmed response. Some achieved lower than 20% reduction of their volumes, but they still achieved some reduction, just not enough to meet that benchmark.

And the other thing that was interesting about this study is that it showed that continued treatment with mirdametinib also provided durable responses. It wasn't that the tumors shrank and then started growing back, but that most patients, about 96% of the patients, had a confirmed objective response that remained durable for up to at least 18 months, if not more at the data cutoff, is what they reported. But they're probably still having people with durable responses right now, and hopefully they'll publish more long-term data on that as well.

And in terms of clinical benefits, so it's not just making the MRIs look better, but also improving symptoms. They evaluated pain and function, as well, and most people that took the medication had improvement of both of these 2 functions. So overall positive, not everyone had a significant reduction in the volume or a significant improvement in their clinical function, but overall pretty good considering a safe administration of mirdametinib.

Dr Hirbe: Excellent. Are there factors about the different MEK inhibitors that can affect compliance, specifically thinking about how the drugs are dosed? Maybe we can each comment on that.

Dr Romo: Sure. I think there's a couple of things that Dr Meade mentioned before. One is that with selumetinib, for example, before it was recommended that you took it only on an empty stomach, so that was a little bit of a problem for some patients, to have to fast before and after you took the medication. Now, more recently, that recommendation has been removed, and people can take selumetinib with or without food. We know that there's maybe a small decrease in the absorption of the medication and that's why it was initially recommended without food, but it is still something that you can do now. And so that improved things.

And the other thing was the capsule problem that kids sometimes struggled with swallowing capsules, so that was a problem with compliance, but now with mirdametinib having a soluble option, that's much easier.

Selumetinib needs to be taken twice daily just like mirdametinib. The doses in both cases are calculated based on your body surface area, so it's not much different in that perspective. Mirdametinib can be dosed continuously or 3 weeks on, 1 week off. With selumetinib, it’s daily. I think the mirdametinib, the randomized study was 3 weeks on, 1 week off. I don't know if that helps with compliance or makes it confusing for some patients. I've noticed that, is this my week off? Is this my week on? might make it a little bit challenging, as opposed to daily dosing with selumetinib, which is just, you know you have to take it. But I'm interested in hearing your opinion, Dr Hirbe and Dr Meade, about that.

Dr Meade: Yeah, definitely a medication that has an “on” period and an “off” period, there are always a little bit of variability when it comes to remembering or forgetting. And I've actually had patients just take their medication into their off period and then halfway through realize like, oh, I should have stopped on Monday. It's Thursday. One of the things that is fortunate is that, children have very quick metabolisms and for a lot of kids, if they do take additional medication, they're not going to experience terrible or severe side effects. They may get a little bit more of a rash.

I've actually found that the patients that we have here don't tolerate a full week off very well. They seem to have some unique side effects, such as nightmares or night terrors. And this has happened to me with more than one patient, where at the end of the off week, they seem to have consistent monthly worsening feelings and irritability. And we've actually started to shorten the off week in order to mitigate that. That's been a unique finding.

I find, interestingly, I think women find this a relatively easy concept, because it seems to overlay with the way oral contraceptives are taken: 3 weeks on, 1 week off, is not a foreign concept to my patients who are women. Though I will say that the way the drug is delivered is not in a blister pack where you have your 3 weeks and then your control week placebo. I think that that's something that companies are creating workarounds, with larger pill cases and reminders and calendar settings, to help people recognize the “on” versus the “off” with mirdametinib.

And then selumetinib, we find that people in general, it's on autopilot. We typically recommend that people miss no more than up to 10% of their doses, which is about 4 per month, in order to really achieve the desired effect.

Another thing I'll just briefly touch on is dose reductions are, in my opinion on the pediatric side, a little bit more challenging with mirdametinib, because the adult dose is 4 mg and then dose reductions, based upon the strengths that are actually commercially available, are 1 mg reductions. So, you're going 25%, 50%, 75% reductions, versus with selumetinib, because the max adult dose is 50 mg and you have both 10 mg and 25 mg, you can dial in a smaller dose reduction for patients where you still feel like you're getting a therapeutic benefit but reducing some of the side effects. From a practitioner side point, dose reductions are, in my opinion, a little bit more challenging to manage with mirdametinib.

Dr Hirbe: I think these are all really important and interesting real-world issues that we have as clinicians. And I didn't even think about the ease of dose reductions, but that's a really good point.

I will definitely say that the 3 weeks on, 1 week off, I think, has been a bit confusing for patients, and I do worry about that in terms of compliance. And I agree that it would be a good thing for the company to think about a blister pack formulation for that because it certainly would make it easier for the patients.

And similarly, the night terror piece was interesting. I haven't had that with the adult population, but I did notice, and many of my patients brought this up too, I think the rationale behind the 3 weeks on, 1 week off was that overall there might be less toxicity, but it seemed more like side effects kind of flare during that off week. I think it'll be interesting to see how treatment evolves over time in real-world practice.

Can you each just discuss your general approach to a patient with NF1 plexiform neurofibroma? If somebody walks into your clinic with an NF1-PN, how do you think through how you're going to manage that patient, just in general? We can start with the pediatric side and then jump to the adult.

Dr Meade: The pediatric side is an interesting world, in the sense that our NF clinic is run by our incredible neurologists, and they are really the ones who are my greatest referral base. As a pediatric oncologist, when you come to me, you are typically coming to me to start medication because another well-seasoned professional has already identified that you have a problem that cannot be fixed with essentially non-oncologic medication. Most patients, if they're coming to me, they're coming to start.

And oftentimes during the intake, it's important to consider the requirements that you're going to need to show, in order to get an insurance to approve a very expensive, costly medication against the FDA indication. I'm always very clear to say they have NF1 by this criteria, they have a plexiform, and it has been there for this long. It is causing this problem, it is inoperable. When I'm able to structure out my consult that way, I find that it leads to a lot less barriers to getting that medication then insurance approved.

Obviously, I tell families the first thing we need to do is schedule you for things like an eye exam, we need a baseline echo[cardiogram], we need blood work. Having pipelines in place to facilitate that quickly, particularly the eye exam, is very critical. If you send your patient off and ask them to come back with an eye exam, you might as well just see them a year later. Having a method to support them in getting those things that you are asking for done is critical.

And then I tell patients, this is your dose. I hand them the literature, and I say, this medication is going to come to your house. You're going to get a call from me that I've reviewed everything and to go ahead and start, and then these are your follow-ups. That first visit, you really need to have an hour, hour and a half with a patient in order to really set up that success on the ped side. There are a lot of questions and concerns that people will ask. And so when I'm thinking about other providers here who are trying to do this at their institution, don't be afraid to ask for time and infrastructure in order to support your patients.

Dr Hirbe: Outstanding. Dr Romo, how about you?

Dr Romo: Yeah, so very, very similar. I think one of the first things, and I said this before, is I just want to make sure that there's no cancerous transformation. My first step is to just make sure that there's no concern for cancer and then if there is no concern for cancer, and I'm pretty sure that this is a benign plexiform neurofibroma that we're dealing with, then I have a few questions for the patient: is it growing or is it not growing in your subjective experience? And more objectively, if you have MRIs from other institutions, can I see those MRIs and assess with measurements, the growth rate, if there has been growth rate or not? Also, where is the tumor located? Is it operable or not operable? And really is it bothering you or is it not bothering you? And in many cases the answer is, it's not bothering me, it's not growing, and I don't feel it's cancerous. We might just monitor.

But if it's benign, it's progressing, and it's about to cause trouble or already causing symptoms, then I counsel them on the treatment options beginning from something as simple as starting gabapentin to help with pain, if that's the main problem, to actually considering a multi-tiered approach where we might need debulking plus MEK inhibitor for example. That’s rarely the case, but in some cases that might be necessary. And if a MEK inhibitor or cabozantinib, for example, which I've mentioned before is necessary, then I approach that and explain what the pros and cons are of each option. And fortunately, if I have access to a clinical trial, which I often do, I always offer, these are the clinical trial options that we have available and that you might meet criteria for, let's look into that if you're interested. And so, I always offer that if possible.

One thing I discuss with my patients, not because I want to use it but because they might read about it, is the role of radiation therapy for a benign plexiform neurofibroma. And in most cases, I think most people would consider radiation to be contraindicated. So, I don't use radiation therapy for benign plexiform tumors. It’s a different story if we're talking about an MPNST [malignant peripheral nerve sheath tumor], but that's something I just tell my patients: I'm not talking to you about this, not because I don't know about it, it's just that we don't use it and it's just going to increase your risk of secondary cancerous transformation years later and we don't know it to be very effective, anyway, for plexiform neurofibromas.

Dr Hirbe: They're all really good points that both of you have made. I'll summarize this segment, we've gone over the data from the ReNeu trial, which had both an adult and pediatric arm that showed a durable response rate of about 45%-ish in both arms. And similarly, both arms had improvement in patient-reported outcomes, which is great for our patients. Some of the nuances of mirdametinib being given with this 3 weeks on, 1 week off are something that we'll have to tackle clinically and how that impacts compliance. A positive point for mirdametinib is that pediatric formulation, or it can even be used in adults, some adult patients have difficulty swallowing a capsule, so it is nice to have an option for that patient population.

Thank you both for sharing your insights and thank you to the audience for watching. Please join us for part 3 of the discussion and we'll start to tackle some of the future therapeutic options for NF1 plexiform neurofibromas.