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

Rene Y. McNall-Knapp, MD

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. 

On February 11, 2025, the FDA approved mirdametinib (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.1 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%).2

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

OncLive: 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?

McNall-Knapp: 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 New England Journal of Medicine. 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.

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 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
2. 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