Targeted therapies called MEK inhibitors are changing the treatment landscape for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN).

NF1-PN are benign tumors that develop in the sheath surrounding nerve cells of the peripheral nervous system. Although they are noncancerous, they may cause various complications depending on their location and how they affect local nerves, bones, and tissues.

Management of NF1-PN typically involves a multidisciplinary team of experts who provide symptom-specific care based on an individual’s needs. Historically, treatment for the underlying tumors themselves was limited to surgical removal. However, some data suggests that up to 1 in 3 people have tumors that are considered inoperable.

In recent years, a new type of medication — MEK inhibitors — has become available to help treat NF1-PN in children whose tumors are not suitable for surgical removal. The first of these medications, selumetinib (Koselugo), was approved in 2020 and paved the way for various other drugs currently being studied for use in NF1-PN.

This article discusses advancements in the treatment of NF1-PN, including the evidence supporting selumetinib and other agents currently under investigation to help individuals with this disease.

After more than 30 years of research aimed at finding a treatment for NF1-PN, selumetinib — a twice-daily oral medication — became the first treatment option available for children with inoperable NF1-PN tumors.

Selumetinib is an MEK inhibitor, which works by inhibiting a group of proteins called mitogen-activated protein kinase kinases 1 and 2 (MEK1 and MEK2). These help regulate signaling pathways within cells that control cell growth, division, and death.

In people with NF1-PN, some of these pathways become overactive, which can lead to dysregulation of cell growth and the formation of tumors. Researchers, therefore, were interested in understanding how inhibiting these pathways with MEK inhibitors such as selumetinib may disrupt tumor growth in people with NF1-PN.

The approval of selumetinib considered the results of the SPRINT study, which included 50 children and adolescents ages 2 to 18 years. In this study, 72% of participants responded to treatment, meaning their tumor volume shrunk by at least 20% with selumetinib.

Another study from 2022 involving 25 children with inoperable NF1-PN found that nearly three-quarters had tumor shrinkage with selumetinib treatment. Among the people who responded to treatment, 86.6% had no disease progression after nearly 2 years of treatment. This study also examined the effect of treatment on NF1-PN complications and found that self-reported pain intensity also decreased significantly.

The success of selumetinib in NF1-PN has spurred research into the use of other MEK inhibitors, including mirdametinib, for treating the condition.

Researchers evaluated the use of mirdametinib in a 2021 study that included 19 people with NF1-PN. Unlike the selumetinib trials, which included only children and adolescents, participants in the study of mirdametinib ranged from 16 to 39 years.

In this study, 42% of people had at least 20% shrinkage in tumor volume with midrametinib treatment, and an additional 53% had stable disease (no change in tumor size). Participants also reported reductions in pain intensity.

Another study investigating the safety and efficacy of mirdametinib is currently underway. This research includes both adults and children ages 2 years and older with NF1-PN. Preliminary results have reported response rates of 52% and 41% in children and adults, respectively, with improvements observed in pain, physical function, and quality of life.

Once the primary part of the trial is complete, the Food and Drug Administration (FDA) will decide whether to approve mirdametinib for the treatment of NF1-PN.

Various other MEK inhibitors, such as trametinib and binimetinib, have been or are currently being studied for their use in NF1-PN treatment.

Doctors currently use trametinib to help treat various cancers, including certain types of melanoma and non-small cell lung cancer. There is a lack of formal studies investigating its use in NF1-PN, but it has been used off-label, and case reports are available.

A review of the available evidence, which included results for 92 people with NF1, found that an estimated 45.3% of people with PNs or NF1-associated gliomas (tumors in the brain or spinal cord) responded to treatment.

Binimetinib, which doctors currently use to help treat melanoma, is also being investigated in a phase 2 study involving adults and children with NF1-PN. Results are due in 2025.

The approval of selumetinib has revolutionized the treatment of children with inoperable NF1-PN tumors. Following this important advancement in the NF1 treatment paradigm, researchers have been studying various other MEK inhibitors for their use to help treat both children and adults.

While more work is still necessary, these efforts represent important advancements in the treatment of NF1-PN, particularly for individuals with previously limited options.