This month, our discussion focuses on the clinical management of plexiform neurofibromas in the era of selumetinib, a MEK inhibitor medication that was approved by the FDA in 2020 for the treatment of inoperable plexiform neurofibromas in children with NF1 aged two to 18.

Features and Potential Complications of Plexiform Neurofibromas

Plexiform neurofibromas, which affect more the 50% of people with NF1, are tumors that often involve multiple branches of either large or small nerves. They can be located on the surface of the body where they are easily visible, sometimes as cords of nerves under the skin or may be deep inside the body and detected only by imaging or if they cause symptoms. The skin around plexiform neurofibromas can sometimes be pigmented and may appear as a large café-au-lait spot with jagged edges. These tumors grow primarily during childhood, though some can grow in adulthood. If plexiform neurofibromas are small and superficial, we monitor them during annual clinic visits. Larger plexiforms are imaged using MRI and followed in the clinic every six to 12 months, or less often if they are stable and not causing symptoms. In the past, surgical removal of plexiform neurofibromas was the only treatment option. However, surgical removal of these tumors in patients who do not have symptoms is usually not recommended due to the risk of complications, primarily because of nerve and blood vessel involvement in these tumors. Surgery is reserved for cases in which important structures are affected, such as the need to relieve pressure from the tumor on the airway or spine. Also, it is not possible to surgically remove the entirety of the tumor, and many eventually grow back after surgery.

Treatment of Plexiform Neurofibromas with Selumetinib and other MEK Inhibitors

For individuals with symptoms due to plexiform neurofibromas, the availability of MEK inhibitors, including the FDA-approved drug selumetinib, has opened new opportunities for treatment. These medications block the activity of one of the components of the RAS/MAPK cellular signaling pathway, which helps to control cell growth and division and is hyperactive in individuals with NF. The availability of MEK inhibitor drugs such as selumetinib, marketed under the brand name Koselugo, underscores the question: When is it appropriate to treat plexiform neurofibromas with these medications? The answer is that if a plexiform neurofibroma cannot be surgically removed and is either causing symptoms, is disfiguring, or is progressing in a manner that symptoms are likely to occur, we consider using selumetinib.

Before beginning the medication, we must be sure that the patient will be compliant with treatment and understand that these oral medications have potential side effects that include problems with heart function, vision, skin, and the gastrointestinal tract; the drugs can also elevate liver enzymes as well as the enzyme CPK (creatine phosphokinase). Because of this, patients taking MEK inhibitor drugs receive regular echocardiograms, ophthalmologic examinations, and blood tests to monitor for these side effects. Skin-related side effects may include an acne-like rash as well as fingernail and toenail bed infections; medications are available to control these side effects and are often helpful. GI symptoms, including diarrhea, occur in some patients. The decision to begin selumetinib is made after discussions with the patient’s family about the potential benefits and risk of side effects.

Upwards of 70% of treated plexiform neurofibromas reduce in size by 20% in volume, if not more. It can take six to 12 months for the reduction in tumor size to be visible, and side effects can occur sooner than this. Some patients find that pain associated with some plexiform neurofibromas tends to improve before the visible reduction in tumor size occurs. After a patient has taken selumetinib for a period of time, often around six months, a repeat MRI may be performed to look for evidence of tumor reduction.  It should be noted that, because it takes time to see tumor shrinkage, selumetinib treatment is not appropriate if there are immediate needs to relieve a critical symptom such as spinal cord or airway compression.  These problems cannot wait months to be resolved, so surgery is necessary, though after healing, medication might be used to treat residual tumor.

We work with the UAB oncology group to manage patients on selumetinib, including monitoring for side effects. While this medication is not a cancer drug, oncologists are familiar with the medication and the management of side effects. UAB and Children’s of Alabama pediatric neuro-oncologist Katie Metrock, M.D., follows children who are on selumetinib. Although the medication is FDA-approved for use in children, we have also used it in adults with symptomatic or progressive plexiform neurofibromas, and some have responded well; adult patients who are candidates for treatment are referred to UAB medical oncologist Vanessa Eulo, M.D.

Information about long-range tolerance of selumetinib, or at what point patients can safely withdraw from treatment without risk of tumor regrowth, is still being determined. We know that stopping the medication typically results in regrowth of the tumor, though it will take more time to see if there comes a point where a person can safely discontinue treatment without facing a risk of tumor regrowth.  There are other drugs that function as MEK inhibitors for which clinical trials have shown efficacy. Selumetinib, however, is the only drug FDA approved for use in children with NF1; we don’t know at this time how the other medications compare with selumetinib.  The question of whether selumetinib is effective for other tumor types in NF1 patients, such as cutaneous neurofibromas, was being investigated in a UAB NF clinical trial, although the trial had to be stopped as recruitment goals were not met. Analysis of data from those who did complete treatment is underway.  A clinical trial of a topical form of MEK inhibitor is also being done at various institutions (though not currently at UAB), with the results awaited.

In summary, the availability of medication to treat plexiform neurofibromas has truly transformed the approach to the care of individuals with NF1 who have these tumors.  There is, however, much more to be learned about the optimal ways to treat individuals with NF1, and clinical trials continue to explore such approaches.  We are also hopeful that future research will identify additional approaches that can be used to treat or prevent complications of NF1.