Rene Y. McNall-Knapp, MD, is a pediatric hematologist-oncologist at Jimmy Everest Center at Oklahoma Children’s Hospital OU Health and professor in the Department of Pediatrics at the University of Oklahoma Health Sciences Center.

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.

Dr McNall-Knapp on HRQOL Outcomes With Mirdametinib in NF1-PN

“There was significant [HRQOL] improvement [from baseline to week 13] in all patients [who received mirdametinib] when you looked at the adults and the parent reports of the childrens’ outcomes in the total score.”

Rene Y. McNall-Knapp, MD, pediatric hematologist-oncologist, Jimmy Everest Center, Oklahoma Children’s Hospital OU Health; professor, Department of Pediatrics, University of Oklahoma Health Sciences Center, discusses health-related quality of life (HRQOL) outcomes from phase 2b ReNeu trial (NCT03962543) investigating mirdametinib in patients with neurofibromatosis type 1–associated symptomatic inoperable plexiform neurofibroma (NF1-PN).

This analysis used the PedsQL 4.0 Generic Core Scales questionnaire to assess HRQOL in patients with NF1-PN. This questionnaire included an assessment of 4 functioning subscales: physical functioning, social functioning, emotional functioning, and school/work functioning. Investigators compared the HRQOL scores reported by patients and patient proxies at cycle 13 with those reported at baseline and observed a significant improvement PedsQL Total Score in all pediatric and adult patients who received mirdametinib. This improvement began as early as cycle 3 and was sustained at most time points through cycle 13. Overall, among patients who could have achieved a clinically meaningful improvement in HRQOL from baseline to week 13 with mirdametinib, 37%, 45%, and 47% of adult patients, pediatric patients (patient-reported), and pediatric patients (parent proxy–reported) achieved this clinically meaningful improvement.

Subscale QOL assessments showed significant improvements in physical functioning across all patient subgroups. Furthermore, significant improvements were seen in emotional functioning among pediatric patients by parent-proxy report and in school/work functioning were among adult patients.

An assessment of patients with a QOL detriment at baseline showed that approximately one-third of pediatric and adult patients who responded to mirdametinib treatment had a clinically meaningful response in each subscale. Additionally, approximately one-half of pediatric patients had clinically meaningful responses in each subscale. McNall-Knapp concluded by explaining that these subscale outcomes were likely caused by the disease only affecting a single facet of each patient’s life.

McNall-Knapp reports receiving institutional research funding from AstraZeneca; Incyte; Jazz Pharmaceuticals; Pfizer; and SpringWorks Therapeutics, Inc. The ReNeu trial was sponsored by SpringWorks Therapeutics, Inc.

Rene Y. McNall-Knapp, MD, discusses HRQOL outcomes from the ReNeu trial investigating mirdametinib in patients with NF1-PN.

Rene Y. McNall-Knapp, MD

Articles

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

Dr McNall-Knapp on HRQOL Outcomes With Mirdametinib in NF1-PN