FDA Approval of Mirdametinib Reduces Treatment Barriers for Adult Patients With NF1-Associated PNs

Following the February 2025 FDA approval of mirdametinib (Gomekli), adult patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PNs) will experience an easier path toward treatment, bypassing the challenges associated with off-label use, according to Timothy Gershon, MD, PhD.1

The indication, which included adult and pediatric patients 2 years of age and older with NF1 and symptomatic PN not amenable to complete resection, distinguished mirdametinib as the first and only agent to be approved in both adult and pediatric patients with NF1-associated PNs.2 Data from the phase 2b ReNeu trial (NCT03962543), which supported the approval, demonstrated that adult patients (n = 58) who received mirdametinib experienced a confirmed overall response rate (ORR) of 41% (95% CI, 29%-55%); the confirmed ORR among pediatric patients who were at least 2 years old (n = 56) was 52% (95% CI, 38%-65%).1

“[This approval] has expedited the flow-through for patients, because with an FDA-approved agent the provider can prescribe it, know that it’s going to be covered, and move on with patient monitoring and care,” Gershon said in an interview with OncLive®. “Prior to [this approval], this was something a community provider couldn’t do because they wouldn’t be able to convince the insurance company that this was a legitimate use of the drug. [This regulatory decision] has decreased the obstacles to getting care for adult patients with NF1-associated PNs.”

Gershon is a professor in the Department of Pediatrics at Emory University School of Medicine, as well as the director of the Children’s Center for Neurosciences Research and a member of the Cell and Molecular Biology Research Program at Winship Cancer Institute of Emory University, both in Atlanta, Georgia.

In the interview, Gershon discussed the historical obstacles to care for adult patients with NF1-associated PNs, the significance of the FDA approval of mirdametinib for these patients, and future research directions for this patient population.

OncLive: What are the barriers to treatment for adult patients with NF1-associated PNs?

Gershon: The greatest obstacle for these [patients] is finding providers with expertise in neurofibromatosis care who also see adults. Generally, the issue is that pediatric neurologists and neuro-oncologists are familiar with neurofibromatosis but work at institutions with age cutoffs [for patients]. Many institutions won’t allow pediatric neurologists and oncologists to see patients over whatever the age cutoff is.

As a result, these patients are [seen] in the adult medicine world. In the adult medicine world, providers tend to be configured to care for patients with more common [diseases] and are less versed in care for patients with relatively [uncommon] genetic disorders. If you are busy taking care of patients with hypertension, it’s hard to take an hour out of your day to take care of a patient with a PN.

[However], child neurologists are also credentialed to care for adults with neurological complaints. I have provided care to adults with neurofibromatosis and PNs. Prior to mirdametinib being [approved], the only FDA-approved agent for neurofibromatosis care was selumetinib [Koselugo], which was approved only for [pediatric patients].

[This led to] constant battles with insurance companies who would deny coverage for selumetinib for adults by saying it wasn’t FDA approved for them, and this was an off-label use. It became very difficult to document that there was enough reason to use selumetinib in adults that it should be covered by insurance. All of that has changed with the FDA approval of mirdametinib in both [pediatric] and adult patients.

How can patients being treated with MEK inhibitors in the community setting receive the proper care?

There’s no reason that a community provider can’t safely monitor a patient on a MEK inhibitor. It’s a matter of making the care algorithm clearer for the community provider. [Although] I’m comfortable prescribing MEK inhibitors for adult patients, it’s more [due to] my experience than my training.

The key is offering materials to community providers that can increase their [comfortability]. [They need] a simple algorithm for dose adjustments in response to findings from [patient] monitoring. [These] findings are likely all that are needed for a community provider to be able to safely prescribe these agents.

What are some strategies for managing the toxicities associated with mirdametinib and other MEK inhibitors?

In my experience, all MEK inhibitors have a similar adverse effect [AE] profile, including trametinib [Mekinist], selumetinib, and mirdametinib. I haven’t seen a [significant safety] benefit with switching from one to another.

However, the mirdametinib regimen is different than the selumetinib regimen. Mirdametinib was tested and validated in ReNeu using a 3-weeks-on, 1-week-off regimen, in contrast to selumetinib, which was validated in a trial where it was administered continuously. This difference is important because the milder AEs such as rash, nausea, and alopecia are unwelcome but not urgent. These tend to get better during that off week, and it may be a reasonable strategy to push through the 3 on-weeks, let the AEs improve in the off-week, and go back on [treatment] the next on-week.

In patients with AEs from mirdametinib [for whom] the one week off isn’t enough of a break to make their AEs tolerable or for those on selumetinib who are having AEs and don’t have an off-week to look forward to, [AE mitigation] strategies can include ancillary medications to minimize the skin issues or dose reduction.

How do you manage expectations for patients who are receiving MEK inhibitors?

It’s important to explain to patients that there’s great heterogeneity in responses. For some patients, PNs respond well [with treatment] and for others they shrink only a bit. Depending on the reason the patient is taking the medication, it’s possible that a relatively small change in tumor size will result in a large change in their quality of life.

For patients with symptomatic PNs with pain, a small decrease in tumor size is often enough to [lead to] a big change in their pain [level], which I explain to my patients. If a patient’s symptom is disfigurement, a small reduction in the size of their PN may not meet their expectations or address what they experience as disfigurement.

It’s important to recognize the heterogeneity of patient complaints. Some have pain, some have disfigurement, and some have other issues. Some patients experience more substantial tumor volume reduction and others have less substantial tumor volume reduction. [Additionally], some patients [being treated with] MEK inhibitor therapy have responses relatively early in the treatment course and others on the same therapy don’t have a change in PN size until relatively late in the course. [Patients need to] understand that it requires a long duration of therapy and the potential for tumor volume reduction is variable.

Is there any ongoing research with the potential to expand treatment options for this patient population?

There are many different research directions. The [unmet] needs of patients with neurofibromatosis are [numerous]. One of these is understanding the neuropsychosocial aspects of neurofibromatosis. There’s a higher risk for autism and learning differences that require differentiated education. Understanding which patients are more likely to have these neuropsychosocial aspects of the disorder would be helpful. We don’t know how to link specific NF1 genotypes to neuropsychosocial phenotypes and that needs to be done.

[In terms of] PN treatment, surgery remains an important option. How surgery and MEK inhibitor therapy should go together is an area that needs to be sorted out. In a patient who undergoes resection and is at risk for recurrence, can a MEK inhibitor be added after surgery in order to prevent the tumor from [recurring]? This needs to be formally studied and hasn’t been yet.

Lastly, are there other drugs that could be added in parallel with MEK inhibitors to [achieve] more consistent and higher magnitude tumor shrinkage? This is an important subject that needs more study.

References

1. FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. FDA. February 11, 2025. Accessed August 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic
2. SpringWorks Therapeutics announces FDA approval of Gomekli (mirdametinib) for the treatment of adult and pediatric patients with NF1-PN. News release. SpringWorks Therapeutics. February 11, 2025. Accessed August 6, 2025. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-fda-approval-gomeklitm