Dr McNall-Knapp on the Efficacy of MEK Inhibition in NF1-Associated PNs

“If [a patient is] dealing with pain, or you’re trying to keep the tumor from growing and being life threatening, these drugs are wonderful. They’ve [been shown to] quickly help with pain and [other] symptoms. [However], if [the challenges the patient is] dealing with are mostly cosmetic, these drugs can be disappointing. You don’t get quite the shrinkage you would hope to see [based on] some pictures in the publications.”

Rene Y. McNall-Knapp, MD, a pediatric hematologist-oncologist at the Jimmy Everest Center at Oklahoma Children’s Hospital Oklahoma University Health, discussed the benefits and limitations of MEK inhibitors for the treatment of pediatric and adult patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PNs).

Therapeutic prospects for patients with NF1-associated PNs improved in 2020, when the MEK1/2 inhibitor selumetinib (Koselugo) received FDA approval for pediatric patients with symptomatic, inoperable PNs, becoming the first agent to demonstrate clinically meaningful benefit in this population, McNall-Knapp began. However, the pediatric‑only label for selumetinib created a coverage gap: insurers often denied access to this agent for adults in this population, she noted. Most recently, in February 2025, 

the FDA approved the second‑generation MEK inhibitor mirdametinib (Gomekli)

 for the treatment of both pediatric and adult NF1‑associated PN populations. 

Different MEK inhibitors offer similar therapeutic values, such as halting tumor growth and rapidly reducing PN‑related pain, functional limitations, and other morbidities, McNall-Knapp said.

Additionally, a proportion of treated patients achieve radiographic shrinkage, although dramatic regressions comparable with images reported in peer-reviewed journals remain uncommon in routine practice, she explained. Consequently, expectations regarding the benefits of these agents should be adjusted depending on treatment goals, McNall-Knapp stated. MEK inhibition is highly effective for symptom control and disease stabilization, but less reliable for purely cosmetic debulking, she summarized.

NF1-associated PNs are also a heterogeneous disease, according to McNall-Knapp. Lesions may encircle major airways or compress pelvic organs, rendering resection impossible, she stated. In such settings, these therapies are invaluable, although patients seeking aesthetic improvement may be disappointed by limited volumetric change, she concluded.

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Rene Y. McNall-Knapp, MD, discusses the current treatment paradigm for pediatric and adult patients with NF1-associated PNs.

Multidisciplinary collaboration is key for addressing both disease burden and symptoms in patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PNs) across adult and pediatric populations, and available therapies are associated with individualized benefits and toxicity profiles, according to Rene Y. McNall-Knapp, MD. 

 (Gomekli) for the treatment of adult and pediatric patients at least 2 years of age with NF1 who have symptomatic PN that are not amenable to complete resection.

 This regulatory decision was backed by data from the phase 2 ReNeu trial (NCT03962543), in which adult patients who received mirdametinib (n = 58) achieved an overall response rate (ORR) of 41% (95% CI, 29%-55%), and pediatric patients treated with this agent (n = 56) had an ORR of 52% (95% CI, 38%-65%).

Notably, the most common grade 3 or higher treatment-related adverse effects (AEs) reported in adult and pediatric patients, respectively, were dermatitis acneiform (9%; 2%), fatigue (1%; 0%), increased blood creatinine phosphokinase levels (1%; 7%), diarrhea (0%; 2%), and decreased ejection fraction (0%; 2%).

“[Mirdametinib is] a great option for patients to at least have an agent to try,” McNall-Knapp said in an interview with 

®. “They may not get as much [tumor] shrinkage, but if we’re trying to control pain, it’s effective for that.”

In the interview, McNall-Knapp discussed the symptom management benefits and cosmetic drawbacks often associated with NF1-associated PN therapies; the importance of treating patients early in the disease course; AE monitoring and management strategies; potential future research directions that may lead to the use of combination regimens; and the importance of multidisciplinary collaboration when caring for patients with NF1-associated PNs.

McNall-Knapp is a pediatric hematologist-oncologist at the Jimmy Everest Center at Oklahoma Children’s Hospital Oklahoma University Health in Oklahoma City.

: What comprises the current treatment paradigm for patients with NF1-associated PNs, and what are the most prevalent challenges associated with delivering therapy to these patients?

: The good news is, we have therapies available now for PNs. In 2020, selumetinib [Koselugo] was [FDA] approved [for pediatric patients with NF1 with symptomatic, inoperable PNs] and was the first effective drug [for this indication]. [Then, in 2025], mirdametinib was FDA approved for both pediatric and adult patients [with NF1-associated PNs]. [After] selumetinib, was approved [specifically] for pediatric patients, that left us with a big gap for insurance coverage sometimes. [Insurance companies] didn’t want to cover the adults because [this agent was not] approved for that [population]. 

PNs [poses a treatment] challenge. They can [arise] anywhere in the body. I’ve had [patients with PNs] that were causing significant respiratory issues, as well as some that surrounded all the organs in the pelvis and were not amenable to surgery.

Having [therapies] that at least stabilize the tumors is great. In some cases, I’ve seen nice shrinkage. [These responses are] not as exciting as one would hope they would be from the pictures in the 

. Those are the best responses. However, if [the patient is] dealing with pain, or you’re trying to keep the tumor from growing and being life-threatening, these drugs are wonderful. They’ve had good results in quickly helping with pain and [other] symptoms. [However], if [the challenges the patient is] dealing with are mostly cosmetic, these [MEK inhibitors] can be disappointing. You don’t get quite the shrinkage you would hope to see [based on] some pictures in the publications.

What is the importance of having mirdametinib approved for the adult population?

Pediatric oncologists used to feel that it was more important to [manage] PNs in pediatric patients. I still think the earlier [in life] we can treat [patients], the better, [and perhaps we] can get more response and better shrinkage. Additionally, if we [manage PNs] early, [patients may experience fewer] AEs with MEK inhibitors, so they tolerate therapy better. [However, PNs] can grow—not in a malignant way—and still be morbid in adults. [The adult indication for mirdametinib] gives us an option.

The AEs [associated with this agent] are manageable for some patients. The worst AE is rash, and that can be distressing. Especially if you’re treating [patients’] cosmetic [symptoms], having an acne rash can be distressing for patients and defeats the purpose of the cosmesis. However, if they don’t have a significant rash, [mirdametinib is] usually well tolerated. Occasionally, [we see] cardiotoxicity, which is not symptomatic, but just numbers on the echocardiogram.

What is the challenge of balancing treatment efficacy with patient quality of life (QOL) when making treatment decisions for patients with NF1-PN?

[Our treatment decisions factor in] the risks vs benefits of the medication. [I tell] my patients that I don’t know how exactly they are going to tolerate their medication. Some patients have lots of gastrointestinal symptoms, and some have lots of rashes. Some have nothing and do well. If you want to see if [a therapy] improves QOL, you have to try it, and if the AEs are better than the symptoms of the tumor, you’ve got a treatment worth going with. However, knowing when to stop [therapy] is also difficult. Even my patients who’ve had good shrinkage [with an agent] are hesitant to stop it if they’ve tolerated it well, and I like to give them a drug holiday and see what happens.

What AE mitigation and management strategies exist for patients who experience AEs but want to continue receiving therapy?

Because pediatric patients’ parents are involved [in their treatment decision-making] and want to do something, [these patients] are more likely to [look for ways to manage the] AEs instead of just quitting the drug. Skin care is essential, including emollients, climbing the ladder on the strength of the steroid creams you use, and using clindamycin and oral doxycycline to help control the acne. It’s important not to use the drying agents that you would for a pediatric patient with acne, because [those agents] would do the opposite [in patients with PNs]. Sometimes I need to use antiemetics or antacids for abdominal pain, but usually after the first month or two, that gets better. Rash and maybe some fatigue [are common], but in kids, that’s not as much of a problem as in adults. Then, you have to watch for cardiotoxicity and rare eye issues. You’ve got to monitor for those because they can sneak up on you.

What might the future look like for NF1-associated PN management based on ongoing research?

It’s an exciting time. There is fortunately a lot of research in the RAS/RAF pathway, which is controlled by the tumor suppressor gene NF1. Other targets are coming along in that pathway that might be beneficial. Unfortunately, some of them cause activation of the pathway, so we have to be careful and do this [research] in a good way.

However, combination therapies are going to be the future, [which could allow us to] decrease the doses of the MEK inhibitors by bringing in another inhibitor of the same pathway. Those trials are underway, and we’ll see what else [emerges]. I’m attending the NF Conference 2025 [in June], so we’ll see what else exciting is out there.

What is the importance of using a multidisciplinary approach when treating patients with this complex malignancy?

It’s essential to have [an oncologist] who’s comfortable with the medications. I am at a smaller institution, so I helped start our multidisciplinary clinic. Before we had that available, at least having one provider who was passionate about these patients and willing to be the point person [was important]. You have to build experience with the drugs and with the natural history of the neurofibromas to recognize when one might be becoming malignant. You have to know what that feels like and looks like.

[You should be in contact with] at least one person who is interested in that [patient] group, usually at an academic medical center. At the smaller [institutions], an oncologist or neurologist [will usually] be that point person, but then [you also need to gather] a multidisciplinary team to deal with all the other issues [these patients] have. I can focus on the tumors, and our genetics team and neurologists are focusing on other issues that are arising.

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 April 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic

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). 

. 2024;42(suppl 16):3016. doi:10.1200/JCO.2024.42.16_suppl.3016

Articles

Multidisciplinary collaboration is crucial for managing NF1-associated plexiform neurofibromas (PNs) in both adults and children. The FDA's approval of mirdametinib for symptomatic PNs marks a significant advancement, offering a treatment option for patients not suitable for surgery. The ReNeu trial demonstrated promising response rates in both adult and pediatric populations. However, treatment-related adverse effects, such as dermatitis and fatigue, require careful management. Early intervention and a multidisciplinary approach are emphasized to optimize outcomes and manage the complex challenges associated with NF1-PN therapies.

Rene Y. McNall-Knapp, MD, discusses the symptom management associated with mirdametinib and MEK inhibition in NF1-associated PNs.

Mirdametinib Use in NF1-Associated PNs Balances Efficacy and QOL Considerations

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"It’s up to us practitioners to provide good, anticipatory guidance regarding symptom management…and to realize what those AEs are and how to treat them effectively. If we can do our best to ameliorate these toxicities and enable patients to stay on [treatment] for a long time, we’ve done a good job.

Christopher L. Moertel, MD, a pediatric neuro-oncologist, professor, and director the Pediatric Neuro-Oncology Fellowship Program in the Division of Pediatric Hematology/Oncology, medical director of the Pediatric Neuro-Oncology and Neurofibromatosis Programs, co-medical director of the Katie Hageboeck Children’s Cancer Research Fund Clinic, clinical neuro-oncology leader of the Brain Tumor Program, and The Kenneth and Betty Jayne Dahlberg Profssor at the University of Minnesota School of Medicine, discussed the importance of informed, careful, and effective management of MEK inhibitor–associated toxicities for patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PN).

The introduction of MEK inhibitors as a key therapeutic option for NF1-associated PN has necessitated a greater focus on managing associated toxicities to ensure long-term treatment adherence, Moertel began. Patients receiving MEK inhibitors are susceptible to a range of adverse effects (AEs), including ocular, cardiac, dermatologic, and gastrointestinal (GI) toxicities, which can significantly affect quality of life and treatment continuation, Moertel stated. He noted that these agents require extended administration—often for a minimum of 18 months—making effective toxicity management critical.

Therefore, oncologists should adopt anticipatory guidance strategies to educate patients on potential AEs and provide proactive toxicity management when they receive a MEK inhibitor, Moertel recommended. For example, dermatologic toxicities, such as rashes and skin irritation, can often be mitigated with antibiotics, bleach baths, and emollient lotions, he shared. GI toxicity, which may include nausea and diarrhea, can be managed through dietary adjustments and supportive care measures, Moertel added. Recognizing these toxicities early and implementing targeted interventions allows patients to tolerate treatment more effectively, reducing the likelihood of treatment discontinuation, Moertel emphasized.

Despite the efficacy of MEK inhibitors in slowing tumor growth, these agents do not eliminate NF1-associated PN, Moertel stated. There remains significant opportunity for research and innovation in this area, particularly in developing strategies to improve treatment tolerability and enhance therapeutic outcomes, he said. By refining toxicity management protocols and expanding treatment options, oncologists can better support patients in maximizing the benefits of MEK inhibitors and minimizing the effect of these agents on daily life, Moertel concluded.

Christopher L. Moertel, MD, discusses the management of MEK inhibitor–associated toxicities in NF1-associated plexiform neurofibromas.


Dr Moertel on the Importance of Managing MEK Inhibitor–Associated Toxicites in NF1-Associated PN

With the rise of MEK inhibitors as a key treatment option for patients with neurofibromatosis type 1 (NF1)–associated plexiform neurofibromas (PN), it is essential for oncologists to be well-versed in managing associated toxicities, according to Christopher L. Moertel, MD, who added that understanding these adverse effects (AEs) and carefully implementing strategies to mitigate them could ensure that patients stay on therapy long enough to derive full benefit.

“For the general oncologist, my main message is [that if they] know the toxicity of these agents and the standard practice for ameliorating those toxicities well, then they'll have success,” Moertel stated in an interview with 

. “They'll be able to keep these patients on therapy and enable patients to get the most benefit out of it that they can.”

In the interview, Moertel discussed the evolution of NF1-associated PN management, noting the shift away from debulking surgery toward MEK inhibition, highlighting 

 (Gomekli) for the treatment of adult and pediatric patients with NF1-associated PN as a particularly significant advancement for a previously underserved patient population. This agent was approved on February 11, 2025, based on results from the phase 2b ReNeu trial (NCT03962543), which showed significant reductions in tumor volume, improved pain control, and enhanced quality of life.

Moertel also explained the rationale behind utilizing MEK inhibitors in this space, discussed the possibility of combining MEK inhibitors with other targeted therapies, and emphasized the importance of knowing and effectively managing toxicities associated with long-term MEK inhibitor use

Moertel serves as a pediatric neuro-oncologist and professor at the University of Minnesota School of Medicine in Minneapolis, where he directs the Pediatric Neuro-Oncology Fellowship Program and co-leads the Pediatric Neuro-Oncology and Neurofibromatosis Programs.

: What is the current standard of care in NF1-associated PN, and how has the approach to treatment evolved, especially given the symptomatic and variable nature of this malignancy?

 The standard of care in NF1-associated PN has evolved quite quickly over the last 10 years. In the [past], the NF1-associated PN treatment schema was very difficult and usually fell to surgery, which was not very successful most of the time because of the potential of these tumors to regrow. Patients would undergo so-called debulking operations, and the tumor would grow right back again. Over a decade ago, a series of clinical trials were started [in NF1-associated PN]; [these were] mostly headquartered or facilitated by the National Institutes of Health. Quite a lot of work was put into various clinical trials with varying, but mostly middling, success. Then we sat down as a group facilitated by the Children's Tumor Foundation to look at potential drugs [for this patient population], and we came upon MEK inhibitors. MEK inhibitors, at that time, had been [assessed] in some animal models, but we then [investigated this approach] with greater gusto and did some very thorough testing.

Now, the MEK inhibitor landscape has exploded, not just for the treatment of adult malignancies such as melanoma, but also for brain tumors, and now PN. The first to be approved by the FDA was selumetinib [Koselugo]. Most recently, mirdametinib [gained FDA approval]. We’re gratified now to have these drugs available for children and adults with NF1-associated PN. Through both clinical trials and everyday use, [we’ve seen that] they're quite effective in improving the quality of life of these patients,

Why was MEK inhibition specifically investigated as a potential therapeutic strategy for this patient population?

Since the discovery of the NF1gene, we discovered that this gene turned on the MAPK pathway. The individual components of that pathway include RAF or BRAF—which is inhibited in a lot of different cancers. After the activation of MEK, we see activation of ERK. By targeting MEK, we don't have to be super specific, [meaning] we can be selective in MEK inhibition. We found [MEK inhibition] to be tolerable [and effective] at preventing the end result of ERK activation, which causes cell proliferation. We knew that chemical pathway and chose these MEK inhibitors because of their potential.

How does the approval of mirdametinib for both pediatric and adult populations with NF1-associated PN impact treatment accessibility?

First, mirdametinib is available as a pill, but [is] also [available as] a dispersible pill that can become a liquid, which is flavored and palatable. We do have a large subset of patients with oral aversion. There's also a certain segment of patients with NF1-associated PN who have autism spectrum disorder and have more prominent [oral] aversions. For children and people with difficulty with pills, having that orally dispersible liquid formulation is a great thing.

Second, having approval for adults [is a big deal]. For many years now, we've been treating patients off-label with a number of different MEK inhibitors. One can imagine all the gauntlets we have to run through to get insurance approval for off-label medications, so we're grateful to finally have that label for adults [with mirdametinib].

What are the key challenges and unmet needs in the management of NF1-associated PN with MEK inhibitors, and how do current strategies address the associated toxicities?

Although these MEK inhibitors have been a huge hit in NF1-associated PN, they still have toxicity. All these patients are susceptible to potential ocular toxicity, heart toxicity, skin, gastrointestinal [GI] tract [toxicity], and so on. [A MEK inhibitor] is a chronic medication, and we don’t intend for people to take this for only 3 to 6 months. I'm committing my patients to a minimum course of 18 months. We want to facilitate patients being able to [handle] this medication time.

It's up to us practitioners to provide good, anticipatory guidance regarding symptom management. We also need to realize what those AEs are and how to treat them effectively. Skin AEs, [for example], can be prevented with antibiotics or bleach baths and good emollient lotions; GI toxicity can be handled by attention to diet and things like that. If we can do the best we can to ameliorate these toxicities and enable patients to stay on [treatment] for a long time, we've done a good job. Nevertheless, these drugs aren't making NF1-associated PN disappear, and we still have toxicity to deal with. There's plenty of opportunity for discovery in this space to help these patients.

Are there any other potential treatment strategies under investigation for patients with NF1-associated PN based on recent biological insights?

We are gaining more and more knowledge about the biology of neurofibroma cells. We know [that in] NF1-associated PN, there are a lot of mast cells, neutrophils, and other cells that come into these tumors. There's a large fibroblast population, and then, of course, the Schwann cell population. That Schwann cell population performs a lot of cell signaling to attract cells to the tumor. If we think about the different cell signaling pathways, metabolic pathways, and tissue-specific targets that are available to us, there’s a lot of potential for either combination therapies or other more directed therapies.

What are the potential benefits and challenges of combining MEK inhibitors with agents targeting different pathways, such as mTOR or PI3K inhibitors?

I know from personal experience that we're able to combine [MEK inhibitors] with other medicines that have a different mechanism. For instance, mTOR inhibitors or PI3K pathway inhibitors have been used quite commonly in combination with MEK inhibitors and haven't shown a marked increase in toxicity. We've had some experiences with HDAC inhibitors in combination [with MEK inhibitors], and those 2 have been well tolerated. Right now, if we're not hitting the same target repeatedly and not potentiating the MEK agents, the overall toxicity shouldn’t be much more than [expected]. In my clinical experience, we've had good luck with it.

What are the key considerations for managing long-term MEK inhibitor therapy, and how can providers ensure appropriate dosing and toxicity management?

The current treatment paradigm is surgical removal. If this is a limited tumor, we’re not going to cause any AEs with the removal. [We shouldn’t] attempt debulking unless we find ourselves in a life-or-limb or organ-threatening situation. We're then left with MEK inhibition as the main avenue for treatment for these patients. We know that [pediatric patients as young as] age 2 or 3 can tolerate these medications. We know now that we have preparations that can be swallowed by all age groups and people types, so we're in a good place there.

[We have to] make sure that providers who are going to be prescribing these medications are well-educated about the fact that these are chronic medications meant to have patients on them for years. We're not just blasting melanoma or colon cancer. I've seen lots of instances where these agents have been used in higher doses, and patients have experienced some pretty [terrible] toxicity; [however,] they know they've got a [terrible] disease, so they're willing to make the trade-off. If we've got a patient who's going to potentially live with these tumors for the rest of their life, the blasting approach will never work. We've got to be careful and thorough in our premedication evaluations, thorough in our education, and use the resources that are out there. The people who are marketing these drugs have excellent resources for providers and patients to use.

FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection. FDA. Feburary 11, 2025. Accessed March 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic

MEK inhibitors have emerged as a pivotal treatment for NF1-associated plexiform neurofibromas, shifting the focus from surgery to pharmacological management. The approval of mirdametinib marks a significant advancement, offering a new option for both pediatric and adult patients. However, managing the associated toxicities is crucial to ensure patients can remain on therapy long enough to benefit. The potential for combining MEK inhibitors with other targeted therapies is being explored, and understanding the biological underpinnings of NF1-associated PN may lead to further therapeutic innovations.

Christopher L. Moertel, MD, discusses advances and ongoing research in NF1-associated plexiform neurofibromas.

Therapeutic Advances and AE Management in NF1-Associated Plexiform Neurofibromas | Supplements and Featured Publications

Dr McNall-Knapp on the Efficacy of MEK Inhibition in NF1-Associated PNs

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Dr Moertel on the Importance of Managing MEK Inhibitor–Associated Toxicites in NF1-Associated PN

Effective Toxicity Management is Key to Maximizing Benefit With MEK Inhibitors in NF1-Associated PN