The treatment arsenal for patients with neurofibromatosis type 1–associated symptomatic inoperable plexiform neurofibroma (NF1-PN), which affects over half of patients harboring NF1 mutations and can cause significant pain and functional issues, has historically lacked effective alternatives to surgery. Now, the emerging class of MEK inhibitors, driven by recent data with mirdametinib, could provide a much-needed systemic therapy for both adults and children with this disease, according to Angela Hirbe, MD, PhD.

The phase 2b ReNeu (NCT03962543) trial evaluated the efficacy and safety of this highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in both adult and pediatric patients with inoperable NF1-PNs causing significant morbidities.¹ Deemed the largest multicenter NF1-PN trial reported to date, findings presented during the 2024 ASCO Annual Meeting showed that mirdametinib generated significant responses, with deep, durable reductions in tumor volume; improvements in pain severity, pain interference, and health-related quality of life (QOL); and a manageable safety profile.

The agent was granted priority review status by the FDA in August 2024 for use in adult and pediatric patients with NF1-PN, with a decision date of February 28, 2025.²

“No clinical trial had shown any benefit [with systemic therapies] for patients with these tumors, until MEK inhibitors. This has been a definite need for a long time,” said Hirbe, who is a medical oncologist at Siteman Cancer Center and an associate professor of medicine in the Division of Oncology, Section of Medical Oncology, at Washington University School of Medicine in Saint Louis, Missouri. “If approved, [mirdametinib] will definitely be integrated [into treatment approaches] quickly, because right now we don’t have any FDA-approved agents for adults with PNs.”

In an interview with OncLive®, Hirbe highlighted the significant morbidity and QOL detriment associated with NF1-PN; the efficacy of mirdametinib in reducing tumor size and pain in both pediatric and adult patients as seen in the ReNeu trial; and the potential future roles of MEK inhibitors for post-surgical adjuvant therapy and secondary prophylaxis in this disease setting.

OncLive: What are the distinguishing features and related morbidities of NF1-PN?

Hirbe: PNs are a big problem for a lot of patients with NF1. They occur in approximately half of patients who have NF1. The tumors are typically very large, and they can cause a significant amount of pain. Pain is especially a problem in the adult population. In the pediatric population, we also start to worry based on location that there can be other functional issues with PNs. [This includes neurofibromas] around the eye [that could] impede vision as a child grows, anything in the neck, which is precious real estate as there are so many structures and not a lot of room there. We worry about large neurofibromas in the neck causing airway compromise or pain. [Lastly], there's the aspect of how disfiguring these tumors can be for some patients, especially large tumors that can cause a whole extremity to be larger than the other. It can make simple things like just fitting into clothes difficult for patients. There’s a vast spectrum of problems that these tumors can cause in kids and adults.

How might MEK inhibitors address unmet needs within this patient population?

For a long time, surgery was the only option that we had that showed any benefit [for this patient population]. Obviously, surgery comes with its own risks and challenges. One problem is that, because these tumors tend to be infiltrative, there’s no way to get negative margins. Even after a surgical procedure, it’s just a debulking that’s being done, so these tumors can grow back. It’s not a permanent fix, and certainly comes with risks of bleeding, infection, and scar tissue after surgery.

The [systemic agent] that we were most hopeful about was imatinib [Gleevec], or any kind of medication that would target mast cells within the tumor, because there had been so much preclinical research showing the importance of those cells in the tumor microenvironment in the generation and maintenance of NF1-PNs. Certainly, any of the drugs tested previously have been [supported by] preclinical research that was conducted in the labs but just hadn’t panned out when we looked at them in patients.

What is the role of the MEK pathway in the pathogenesis of NF1-PNs?

Patients with NF1 have a germline mutation in the NF1 gene which codes for neurofibromin. Neurofibromin functions as a RAS GTPase-activating protein, so it helps to turn RAS off. Without neurofibromin, RAS is overactive. [Accordingly], any of those downstream pathways that RAS regulates, which includes the MEK/ERK pathway, are left unchecked.

When I’m talking to patients, I explain that NF1 is like a stop sign, and it tells certain pathways in the body to stop. We’re not smart enough to put that stop sign back, but we can at least target some of those proteins or pathways that the stop sign is trying to [control].

What were the enrollment criteria, methods, and key objectives of the ReNeu study?

ReNeu [enrolled] patients from 2 years of age through adulthood onto a pediatric cohort and adult cohort. Patients had to have inoperable PNs, meaning that they wouldn’t be able to undergo a full surgical debulking or surgery would be off the table altogether due to risks. These tumors also had to be causing significant morbidity. That definition was sort of left up to the providers, but in my mind, [that is] a tumor that’s impinging on an organ, potentially causing compromise of that organ; is large and disfiguring, making even activities of daily living difficult and causing a significant amount of pain. Those are some of the things that I think of when we talk about morbidity caused by these tumors. Patients had to be able to take oral medication, so they couldn’t have any sort of gastrointestinal dysfunction. Otherwise, it was a fairly representative population of all patients with PN.

[This] was an open-label, phase 2 study, so patients received the medication for 3 weeks on and 1 week off. The [primary] end point was objective response rate [ORR], [defined as] tumor shrinkage, and [key secondary end points included] QOL measurements. In the pediatric population, ORR is probably the most significant [measure to evaluate], because we’re hoping to shrink these tumors and keep them from causing problems in adults. The biggest problem that adult patients have is pain. That can be hard to manage and can interfere with their life, so looking at both of those measures is very important.

What were the primary efficacy results from this study? Did any of the data surprise you?

I was surprised that we had as much of an ORR in the adult population as we did. It was [a 41%] ORR in adults and [a 52%] ORR in the pediatric population. The pediatric data [with mirdametinib] were comparable to [that of] other MEK inhibitors evaluated [for NF1-PNs]. I was surprised by that because, generally, these tumors grow more in the pediatric or adolescent population. In adults, when we do [see growth] we start to worry about malignant transformation. Nonetheless, we saw that ORR in both the pediatric and adult population.

I personally enrolled a lot of patients onto this trial; we had [approximately] 12 patients on [the study] and I have 2 patients who are involved in the long-term follow-up. They’ve been on the MEK inhibitor well beyond 2 years at this point and have continued to experience benefit. Those that achieved an objective response haven’t had regrowth of their tumors yet. However, in terms of [response] durability, it’s a bit too early to say anything about that.

What is currently known about the safety profile of mirdametinib?

With MEK inhibitors, the 2 big things that you worry about are rash/skin changes and diarrhea. [Notably], the manifestations [of skin changes] are a bit different in kids than adolescents and adults. Adolescents and adults are more at risk for this acneiform-like rash, which is an inflammatory reaction. Looking historically at MEK inhibitor use, approximately 80% of patients end up having a rash. I work closely with our dermatologist at Siteman Cancer Center [to manage this].

I had gotten burned with other MEK inhibitors in the past, so when I was enrolling patients [onto ReNeu] we put them onto 50 mg of doxycycline daily for 3 months at the start of treatment with the MEK inhibitor. It's a very low dose and is an anti-inflammatory dose rather than an antimicrobial dose. We also gave patients clindamycin lotion to begin using at the time that they started the MEK inhibitor. [On the study] we saw a low incidence of rash, and even those that had rash [had predominantly] mild [cases]. I’m a big proponent of upfront prophylaxis in terms of rash.

When you’re starting a MEK inhibitor, diarrhea is the other big adverse effect [AE] that [occurs in approximately] 20% of patients. It does respond to Imodium, and usually dissipates as the body becomes tolerant to the MEK inhibitor, which is typically after a couple of months.

In the event that mirdametinib gains FDA approval, how will it influence clinical practice?

We have something for the kids, but there’s not an easy path to getting a MEK inhibitor for patients [18 years of age or older]. We’ve been desperately waiting for an FDA approval for the adult population.

These are challenging tumors to treat, and there’s no one perfect algorithm for every single patient. The important thing to keep in mind is that [mirdametinib] is another tool in our toolbox, and we need to think carefully about which tool is the right one to use right now for every patient, whether that’s surgery or a MEK inhibitor or some combination [of the two]. As we continue to do more and more research, I hope that we add more tools to that toolbox.

Is there a potential role for mirdametinib in the adjuvant setting or as secondary prophylaxis?

That’s something that we’re [investigating] with MEK inhibitors in general. Sometimes we’re going to need to do a debulking [procedure] regardless; we know we’re not going to be able to get all the tumor, but some of it’s got to come out. Something that we are starting to look at is whether adding a MEK inhibitor after debulking could reduce the likelihood of that tumor growing back and causing problems in the future.

The other thing that’s being looked at is prophylactic use [of MEK inhibitors] as a kind of secondary prevention [strategy]. [However], we don’t know when to start the medication or how long a patient might need to be on the medication.

References

1. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: a pivotal phase 2b trial of mirdametinib in adults and children with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(suppl 16):3016. doi:10.1200/JCO.2024.42.16_suppl.3016
2. FDA grants priority review to SpringWorks Therapeutics’ new drug application for mirdametinib for the treatment of adults and children with NF1-PN. News release. SpringWorks Therapeutics, Inc. August 28, 2024. Accessed November 5, 2024. https://ir.springworkstx.com/news-releases/news-release-details/fda-grants-priority-review-springworks-therapeutics-new-drug