When should you use MEK inhibitors for neurofibromatosis type 1?

Guidelines on clinical use from an expert who helped write them

An innovative drug class – mitogen-activated protein kinase kinase (MEK) inhibitors – has revolutionized treatment for pediatric patients with neurofibromatosis (NF) type 1. But the considerable side effects of MEK inhibitors make it challenging to know when and how to use them.

National leaders in NF care recently developed guidelines to help physicians navigate challenges like how to identify appropriate patients, lessen side effects and reduce the dosage when necessary. One of these national leaders is Laura Klesse, M.D. Ph.D., Pediatric Hematologist/Oncologist and Director of the Neurofibromatosis Program at Children’s Health℠ and Associate Professor at UT Southwestern.

“For the right patients, MEK inhibitors can make a dramatic difference in mitigating the impact of tumors associated with NF type 1,” Dr. Klesse says. “We follow these guidelines at our center to help ensure that appropriate patients receive these drugs and that those patients have maximum benefit.”

Evaluating patients for a MEK inhibitor

About 50% of individuals with NF type 1 have plexiform neurofibromas. These nerve sheath tumors are benign in children, but they tend to grow as the child grows and can be very large. They can have painful, disabling and disfiguring effects.

In 2020, the FDA approved selumetinib for NF type 1 patients with inoperable plexiform neurofibromas. The pivotal clinical trial that led to its approval showed that the drug was highly effective – more than 70% of patients experienced tumor shrinkage and nearly 100% experienced less pain and better function. However, many patients had severe GI and skin toxicity, and some experienced cardiac toxicity.

“Our goal is to identify patients as early as possible whose benefits of a MEK inhibitor outweigh the risks,” Dr. Klesse explains. Dr. Klesse considers patients to be candidates for MEK inhibitors if her team detects:

  • Tumor growth: Volumetric analysis is the most effective way to detect tumor growth for patients with NF type 1. It enables an oncologist to see two-dimensional growth, which is hard to assess with MRIs. “If your center doesn’t have volumetric analysis available, it’s important to pair the MRI with a clinical evaluation to determine if the tumor is growing,” Dr. Klesse says.
  • Clinical signs and symptoms that show progression: At Children’s Health, Dr. Klesse works closely with an ophthalmologist, neurologist, neuropsychologist and other specialists to evaluate if a tumor is beginning to impact a patient’s organ or ability to function.
  • A tumor in a high-risk location: Orbital and paraspinal plexiform neurofibromas are the highest risk locations because they can cause vision impairment or decreased mobility.

“These patients are high-risk, and we aim to get them on a MEK inhibitor as quickly as possible to hopefully prevent a lot of the tumor growth and morbidity,” Dr. Klesse says.

In most cases, Dr. Klesse is able to identify high-risk patients by age 2 or 3. Younger patients (aged 10 and younger) are higher risk because their growing years are ahead of them. She monitors these patients closely to determine when and if MEK inhibitors are indicated.

Counseling families and proactively mitigating side effects

Unlike conventional treatments that kill tumor cells, MEK inhibitors work by blocking the overactive RAS signaling pathway that causes tumor growth and other NF type 1 symptoms. Research shows that most patients need to take a MEK inhibitor long-term to prevent tumor growth.

“It’s very important to counsel patients and families upfront so they understand why this treatment is recommended for them, what to expect and what will happen if they stop taking it. This typically helps them to keep taking the MEK inhibitor under our guidance, even if they experience some difficult side effects,” Dr. Klesse says.

Dr. Klesse also counsels patients on several medications that aim to mitigate skin and GI toxicity. These medications include:

  • Antibiotics, such as doxycycline, can prevent paronychia as well as the severe acne rash that is more common among teenagers
  • Skin cream can prevent the severe eczema that is more common among young children.
  • Antiemetics and antidiarrheals can help the severe nausea and diarrhea that often occurs in the first two months of treatment.

"Preventing these common side effects is important because once they begin, they are very difficult to treat," says Dr. Klesse. "Patients who can better tolerate the MEK inhibitors are more likely to stay on them."

Toxicity monitoring and when to reduce the dose

In addition to monitoring skin and GI toxicities, these patients also require careful monitoring of cardiac toxicity – the biggest risk of MEK inhibitors – which can cause reduced ejection fraction. This is reversible as long as it’s detected early.

Before a patient begins the MEK inhibitor, the team at Children’s Health performs an echocardiogram to evaluate their baseline cardiac function. Patients receive an echocardiogram one month and three months after starting the MEK inhibitor, and every three to six months after that.

If a drop in cardiac function is detected, the guidelines are to:

  • Hold the MEK inhibitor until the patient’s condition returns to grade 1
  • Restart the MEK inhibitor at a lower dose, typically about 20%-25% of the original dose
  • Reduce the dose by 20%-25% again if necessary 

“Research shows you can reduce the dose without the patient losing benefit from the MEK inhibitor. These adjustments really help patients who experience significant side effects to better tolerate the medication over time,” Dr. Klesse explains.

Measuring the benefit of MEK inhibitors

Patients with NF type 1 often experience dramatic relief even when tumors only shrink a small amount. Dr. Klesse frequently treats patients who fall into this category at the NF program at Children’s Health, one of the highest-volume programs in the U.S.

For example, patients with periorbital plexiform neurofibromas often experience pressure buildup in their eyes. Even if the MEK inhibitor doesn’t significantly shrink the tumor, most patients have reduced pressure and no longer need their eye drops.

Most patients with large plexiform neurofibromas in their legs also experience normalized gait and less sensitivity and pain after taking MEK inhibitors – even without significant tumor shrinkage.

“As oncologists, we love to see tumors shrink and we naturally correlate that shrinkage to clinical improvement, but it’s important not to discount these clinical differences that make such an impact in our patients’ lives,” Dr. Klesse says.

Shaping the future of NF care

As part of the National NF Clinical Trial Consortium, the NF program at Children’s Health is one of 20 sites in the U.S. studying the latest advances in MEK inhibitors and other NF therapies. The promising advances in the pipeline include a MEK inhibitor in a liquid formulation, combination treatments and using a MEK inhibitor for children under age 2.

“The future for NF patients is much brighter than it was just a few years ago before MEK inhibitors. We’ll continue to lead the way in research and be a resource to other oncologists nationwide as treatments and guidelines evolve,” Dr. Klesse says. 

Have a question or complex case you’d like to discuss? Connect with Dr. Klesse >>

Learn more about innovative oncology care at Children’s Health >>

Research Library

Find the latest innovation, clinical trial and research articles.