Justin T. Jordan, MD, MPH, FAAN
The FDA approval of mirdametinib (Gomekli) marked a key milestone for adult patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PNs), with an agent now indicated for the treatment of this population for the first time, according to Justin T. Jordan, MD, MPH, FAAN.
In February 2025, the FDA approved mirdametinib for adult and pediatric patients 2 years of age and older with NF1 who have symptomatic PNs not amenable to complete resection. This approval was supported by data from the phase 2 ReNeu trial (NCT03962543), where the MEK inhibitor generated an overall response rate of 41% (95% CI, 29%-55%) in adult patients (n = 58) and 52% (95% CI, 38%-65%) in pediatric patients (n = 56).
This agent represents another tool to add to the comprehensive support network available for this patient population, Jordan added.
“NF1 is a genetic disorder, and there are entire families [who] have NF1. There are large communities affected by NF1. When a patient is diagnosed, plugging into those communities is important,” Jordan said during an interview with OncLive®. “I can’t say enough how important those organizations are in terms of providing support to patients and families, and in helping spur on research, which is important for our patients.”
During the interview, Jordan expanded on past treatment challenges for adult patients with NF1-associated PNs, delved into the implications of the FDA approval of mirdametinib, and highlighted key management strategies when utilizing MEK inhibitors in this setting.
Jordan is an associate professor of neurology, head of the Neuro-Oncology Section, and an associate professor at the O’Donnell Brain Institute at UT Southwestern Medical Center in Dallas, Texas.
OncLive: For adult patients with NF1-associated PNs, what have been some of the challenges with treatment and drug development for that population?
Jordan: NF1 is associated with PNs in approximately 50% of patients. Those tumors generally involve multiple nerves and nerve fascicles, so [they] are frequently adjacent to or involving large vessels, organs, and deep tissues. Therefore, the long-standing treatment paradigm has primarily been surgical debulking. However, because of those challenges with the tumor, surgical debulking has been limited.
One of the challenges in developing drugs in this space is that, although these are neoplastic [tumors], they’re incredibly slow growing, and that’s frequently a challenge in the oncology world. [We need to] make sure we can create a therapy that can be tolerated for long periods of time with minimal toxicity and controls the growth rate of a tumor. Thankfully, we’re now in an era where we can take advantage of the vulnerabilities of this particular tumor and the pathway alterations related to the NF1 mutation.
What has been the rationale behind exploring MEK inhibition within this space?
This goes back probably over a decade, maybe 2. You have to go back and look at papers from Nancy Ratner, PhD, [of Cincinnati Children’s Hospital in Ohio]. NF1 is a RAS GAP protein, so when NF1 function is lost, RAS is upregulated, [along with] all the downstream pathways, which include MEK.
After looking at a variety of different vulnerabilities in [the MAPK pathway], MEK came to the surface in basic science labs, and [inhibiting MEK] slowly came into in vivo [testing] and then into human practice over the years.
With mirdametinib indicated for both pediatric and adult populations, what are the implications of the FDA approval for the adult population?
Selumetinib [Koselugo] was the first drug FDA approved for NF1-associated PNs, and that’s approved for children 2 years of age and older with inoperable, symptomatic PNs. It’s been on the market for that indication since 2020, and over that period of time, we’ve seen some off-label use [in the adult population] as people have had it available in the armamentarium of therapies.
With mirdametinib receiving an approval that includes adults as well [as pediatric patients], this is really the first time that we have an on-label therapy available for PNs in adults, and it’s tremendous. We have an enormous population of untreated or undertreated individuals whose lives are altered due to disability, dysfunction, and disfigurement related to these tumors. This is an elevating moment in the entire community of NF1-associated PNs, to have therapies [available] and to see hope on the horizon. These are also effective therapies, but now we can build on this with additional opportunities down the line.
Regarding MEK inhibition in general, what should colleagues know about these types of agents and their safety profile within this patient population?
Generally, the safety profile [of MEK inhibitors] is pretty tolerable. As I mentioned before, these drugs were developed with the idea of long-term treatment in mind, potentially for these non-cancerous neoplasms. The most common things that we see are often some gastrointestinal toxicity, some fatigue, and maybe some rash in adults and children.
The more serious [adverse effects (AEs)] that you may want to keep a lookout for would include cardiac toxicity. Cardiomyopathy is a risk. It is often recoverable with drug hold or discontinuation, but we do have to monitor patients closely with echocardiograms. There are also some risks of subretinal fluid [accumulation] that could ultimately lead to retinal detachment. We work very closely with ophthalmologists as well to [monitor] the back of the eyes [for patients]. Those are the two biggest risks [with MEK inhibition].
Given that a treatment such as mirdametinib is meant to be given as a long-term therapy, what are some of the challenges with compliance and strategies to help keep patients on treatment?
My approach is to have an up-front discussion to set expectations for patients. Depending on the literature you look at, success in these trials [of MEK inhibition] was called 20% [tumor] shrinkage. How does the risk:benefit [profile] balance out for [a patient] and their life with the tumor? In my mind, it’s important to set expectations.
It’s important to be very proactive, especially in terms of rash management. Patients with NF1-associated PNs very often, or most commonly, also have cutaneous neurofibromas, which can be painful and disfiguring. When you add acneiform rash and other rash types on top of that, it can sometimes be a bridge too far for some patients. You want to make sure that they are aware that’s going to happen. You want to be very proactive in terms of rash control, and you want to have a very good management plan in place for those safety monitoring tests. It is often the case that patients with NF1-associated PNs have to travel long distances to get expert care, and you want to make sure that you’re not breaking their bank with all of the travel back and forth to get the necessary monitoring and tests.
Following the approval of mirdametinib, what ongoing research could address some other lingering unmet needs for patients with NF1-associated PNs?
In the world of PNs, there is still a population of individuals who don’t respond to MEK inhibition, either with mirdametinib or selumetinib. Therefore, looking for additional lines of therapy—whether it be a new generation of MEK inhibition [or] a combination therapy—still remains a very big question on our minds. From patient surveys, we understand that cutaneous neurofibroma therapy is a huge unmet need that patients care about, and there is a lot of work happening on some device-based interventions for cutaneous neurofibromas, as well as some early work in systemic therapeutics and topical therapeutics.
There are also multiple malignancies associated with NF1. The greatest cause of premature death in NF1 is malignant peripheral nerve sheath tumors [MPNSTs], which are really the malignant transformation of PNs. We have identified that MEK inhibition is not all that effective in MPNSTs, so there is an enormous opportunity for additional therapy. Brain tumors, including high-grade gliomas, are increased in frequency in this population, and there are studies ongoing looking at that. There are a variety of additional [associated] tumors as well that leave a lot of questions to be answered. However, now that we’ve identified an opportunity to take advantage of MEK inhibition and that inherent vulnerability within NF1 loss, we’re steps ahead in terms of looking at how to address those malignancies, as well as other manifestations of the disease.
For patients diagnosed with NF1-associated PNs, what are the key steps for treatment and care planning?
NF1 is certainly a rare disease, but not all that rare. Approximately 1 in 2300 patients have NF1, and PNs happen in approximately half of them. We know that we don’t have enough specialty centers across the country for everyone with NF1 to go to one. There are well-written care recommendations for patients, or [recommendations for] what they should receive at their annual visits, and that can be done in a primary care office, just as in an NF1 clinic. [You need to] make sure that an annual blood pressure check is done because of the risk of pheochromocytoma and renal artery stenosis. Make sure you’re looking for scoliosis, and PNs, and [you should] educate patients on the signs and symptoms of MPNST. I would be remiss if I overlooked the need for early breast cancer screening. It’s recommended in the National Comprehensive Cancer Network [Guidelines] for women with NF1 to begin annual breast cancer screening at age 30 because of the increased risk [associated with] NF1.
All of those things are achievable in a primary care office. Certainly, patients with NF1 get spectacular care when they come to an NF1 center of excellence. However, [clinicians in] any oncology office and any primary care office [should] realize that they can do a great job caring for these patients. We need to come to a care paradigm where the [patients with] the most complicated cases have access to NF1 centers of excellence, and we [needed to] increase the availability of that across the country. [However, we] also need to empower local physicians to be able to provide good screening and recognize when complicated cases arise.
Reference
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 July 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic