MEK Inhibitors for Neurofibromatosis Type 1: A Comprehensive Patient Guide

Table of Contents

• Introduction to NF1 and MEK Inhibitors
• Comparing Different MEK Inhibitors
• Tumor-Specific Uses of MEK Inhibitors
• Plexiform Neurofibromas
• Atypical Neurofibromas
• Malignant Peripheral Nerve Sheath Tumors
• Cutaneous Neurofibromas
• Low-Grade Gliomas
• Juvenile Myelomonocytic Leukemia
• Non-Tumor Manifestations
• Practical Treatment Considerations
• Consensus Recommendations
• Source Information

Introduction to NF1 and MEK Inhibitors

Neurofibromatosis type 1 (NF1) is a genetic condition that affects approximately 1 in 3,000 people. This condition results from changes in the NF1 gene that lead to overactivation of the RAS pathway, which drives tumor formation and other symptoms associated with NF1, including neurocognitive challenges and bone abnormalities.

The recent approval of MEK inhibitors (MEKi) represents a significant advancement in NF1 treatment. These medications work by blocking the overactive RAS pathway downstream. Selumetinib became the first medication approved specifically for inoperable symptomatic plexiform neurofibromas in children with NF1 in the United States, European Union, and other regions.

This comprehensive review examines the current evidence for using MEK inhibitors across various NF1 manifestations. We explore both tumor-related and non-tumor symptoms and provide practical guidance based on the latest clinical research and expert consensus.

Comparing Different MEK Inhibitors

Several MEK inhibitors are available, all derived from similar chemical structures but with important differences in their properties. The five main MEK inhibitors include selumetinib, trametinib, cobimetinib, binimetinib, and mirdametinib. All are taken orally but have varying half-lives (how long they remain active in the body), ranging from approximately 5-10 hours for binimetinib to 3-5 days for trametinib.

These medications share similar side effect profiles, which may include skin rash, inflammation around nails (paronychia), decreased heart function, and laboratory abnormalities such as elevated creatine kinase (a muscle enzyme) and liver dysfunction. While preclinical studies suggested varying abilities to penetrate the brain, these findings haven't reliably predicted effectiveness against central nervous system tumors.

Dosing for NF1 differs significantly from cancer treatment in adults. Most clinical trials for NF1 use lower doses than those approved for adult cancers. Recent evidence also suggests that MEK inhibitors may alter the tumor immune environment, contributing to their effectiveness beyond direct tumor effects.

Currently, formulation availability (particularly child-appropriate versions), insurance coverage, and specific clinical experience with NF1 manifestations are the most important factors distinguishing these medications, as no direct comparison studies have been conducted to evaluate their relative effectiveness or side effect profiles in NF1 patients.

Tumor-Specific Uses of MEK Inhibitors

MEK inhibitors have shown promising results across various tumor types associated with NF1. The response varies depending on the specific tumor type, location, and individual patient factors. Clinical trials have demonstrated particularly strong results for plexiform neurofibromas, with growing evidence supporting their use for other manifestations.

The mechanism of action involves targeting the RAS pathway that becomes overactive due to NF1 gene mutations. This pathway activation drives tumor growth in NF1-related tumors, making MEK inhibition a targeted approach that addresses the root cause of these manifestations rather than just managing symptoms.

Plexiform Neurofibromas

Plexiform neurofibromas (PN) are complex nerve tumors that affect many people with NF1 and can cause significant symptoms including pain, functional limitations, and disfigurement. These tumors develop when the normal NF1 gene becomes inactivated in Schwann cells, leading to RAS pathway activation.

Clinical trials have demonstrated remarkable effectiveness of MEK inhibitors against PN. In a phase 1 trial, selumetinib showed a partial response (defined as >20% decrease in tumor volume on MRI) in 17 of 24 participants (71%). The subsequent phase 2 study showed a 68% response rate (34 of 50 participants).

Perhaps even more importantly, selumetinib prolonged progression-free survival, with no participants showing tumor progression during the first year of treatment despite 21 participants having tumors that were known to be growing when they entered the study. Patients reported meaningful improvements in pain, pulmonary function, strength, and range of motion.

While most participants experienced at least one treatment-related side effect, the majority were mild (grade 1-2) and didn't require dose modification or discontinuation. These results led to regulatory approval of selumetinib for pediatric patients with NF1 and inoperable PN.

Other MEK inhibitors have shown similar effectiveness:

• Trametinib demonstrated a 46% response rate (12 of 26 children) in a phase 1/2A study
• Binimetinib showed 70% response in children and 65% in adults in interim phase 2 trial results
• Mirdametinib showed a 42% response rate (8 of 19 participants) in those aged 16 years and older

While selumetinib remains the only approved treatment for this indication in children, evidence suggests other MEK inhibitors are likely similarly effective. The use of MEK inhibitors for symptomatic PN in adults or for asymptomatic but growing and inoperable PN may be appropriate, though results from prospective studies are still needed.

Atypical Neurofibromas

Atypical neurofibromas (AN) are defined by specific histological features including increased cellularity and cellular atypia without malignant characteristics. Many AN show deletion of the CDKN2A/B genes. These tumors are important in NF1 because they may be precursor lesions that can transform into malignant peripheral nerve sheath tumors (MPNST).

Many atypical neurofibromas show increased activity on specialized PET scans relative to plexiform neurofibromas and frequently appear as distinct nodular lesions on MRI. Mouse models of AN have explored the role of MEK inhibitors alone and in combination with other agents.

Clinical trials have also evaluated responses of these distinct nodular lesions and atypical neurofibromas to MEK inhibitors, suggesting that some may respond to treatment. However, prospective studies are needed to define the response rate and compare efficacy to plexiform neurofibromas and other tumors.

If surgery isn't feasible, treatment of atypical neurofibromas with a MEK inhibitor can be considered given the possibility of response based on preliminary data. Before initiating therapy, ruling out MPNST is absolutely essential, and patients should be closely monitored to assess treatment response.

Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNST) occur in approximately 10% of individuals with NF1, often arising from preexisting plexiform neurofibromas or atypical neurofibromas. These aggressive cancers are the leading cause of death for people with NF1.

Despite inhibition of cell growth in MPNST cell lines with MEK inhibitors, animal models treated with single-agent MEK inhibitors produced limited or no growth suppression. Tumor growth inhibition was transient and resulted in resistance and reactivation of target pathways.

Combination therapy of MEK inhibitors with other targets of interest in MPNST pathogenesis (including mTOR, MNK, BRD, and MET) in preclinical models demonstrated tumor regression with synergistic responses. However, to date, there is no evidence that single-agent MEK inhibitors are effective for treating MPNST.

Anecdotal evidence also suggests that MEK inhibitors do not prevent the development of MPNST, as the development of these malignant tumors has been reported in patients receiving MEK inhibitor treatment. Ongoing and future clinical trials for MPNST will investigate combination therapies with MEK inhibitors.

Cutaneous Neurofibromas

Cutaneous neurofibromas (CN) are skin tumors that affect more than 95% of adults with NF1 and represent a major quality of life concern, constituting a substantial unmet need for people with NF1. Recent research has identified a potential cell of origin for these tumors and uncovered shared developmental pathways between cutaneous and plexiform neurofibromas.

A clinical trial of selumetinib for cutaneous neurofibromas is ongoing, and early reports show that all evaluable participants (6 patients) demonstrated at least a 20% decrease in average cutaneous neurofibroma volume compared to baseline. However, participants also experienced systemic side effects including rash, hypertension, and skin infections that limited treatment duration.

A phase 1 study evaluating three gel concentrations of the topical MEK inhibitor NFX-179 has recently reported good tolerability, leading to a larger phase 2 study. Although MEK inhibitors show preliminary activity against cutaneous neurofibromas, significant work remains to determine the extent of response, optimal delivery methods, dosing, timing, and treatment duration to maximize therapeutic benefits.

Low-Grade Gliomas

Most NF1-associated pediatric low-grade gliomas (LGG) involve loss of both NF1 alleles without the BRAF abnormalities common in sporadic cases. Older children and young adults with NF1-associated LGG may have additional genetic changes including CDKN2A/B and ATRX mutations, which can lead to more aggressive tumor behavior despite maintaining some pilocytic features.

Preclinical studies have supported clinical investigation of MEK inhibitors for low-grade gliomas. Treatment with selumetinib led to decreased tumor volume and longer progression-free survival in models, while mirdametinib decreased tumor volume and proliferation or prevented tumor formation in two mouse models of NF1-associated low-grade glioma.

A phase 2 clinical study of selumetinib included a group of 25 children with recurrent, refractory or progressive NF1-associated low-grade glioma. Of these, 10 children (40%) achieved a sustained partial response (≥50% reduction in tumor size) to selumetinib at the recommended phase 2 dose of 25 mg/m²/dose twice daily. The remaining 15 participants (60%) demonstrated stable disease, and the 2-year progression-free survival was 96%.

For NF1-associated optic pathway gliomas, vision outcomes are as important as tumor control. Among 10 children with recurrent, refractory, or progressive NF1-associated optic pathway glioma treated with selumetinib, visual acuity improved in two (20%) and remained stable in eight (80%). This compares favorably to carboplatin-based therapy, where previous studies showed visual acuity improved in 32%, was stable in 40%, and worsened in 28% of 88 previously untreated patients.

These findings have led to the development of a phase 3 study comparing selumetinib with carboplatin and vincristine in untreated NF1-associated low-grade glioma, as well as multiple phase 2 trials of other MEK inhibitors specifically investigating NF1-associated low-grade glioma.

Juvenile Myelomonocytic Leukemia

Children with NF1 have an increased risk of developing juvenile myelomonocytic leukemia (JMML), a uniquely RAS-dependent leukemia that is currently only cured by stem cell transplantation. Although approximately 10% of JMML patients have secondary mutations in the RAS pathway at diagnosis and relapse, all patients maintain their initiating RAS pathway mutation at high frequency.

This unique dependence on activated RAS signaling has led to extensive testing of MEK inhibitors as a potential therapy. Preclinical studies have investigated the role of MEK inhibitors in genetically engineered mouse models of JMML driven by Kras, Nras, or Nf1 mutations. The results suggest potential benefit, particularly when combined with other targeted agents.

Non-Tumor Manifestations

Beyond tumor-related manifestations, NF1 involves numerous non-tumor symptoms that significantly impact quality of life. These include bone abnormalities, chronic pain, and neurocognitive challenges. The potential effect of MEK inhibitors on these non-tumor manifestations requires careful consideration.

Currently, there is limited robust clinical evidence regarding the direct clinical benefit or potential harm of MEK inhibitor therapy on skeletal manifestations of NF1. Future studies should include careful monitoring of skeletal manifestations in patients receiving these treatments.

Plexiform neurofibroma-associated pain may represent a potential indication for MEK inhibitor treatment, but this should be monitored systematically using validated pain measures. Based on current data, there is no evidence of neurotoxicity with MEK inhibitor treatment in children and young adults, though further studies are needed to evaluate any potential neurocognitive benefits.

Practical Treatment Considerations

When considering MEK inhibitor treatment, several practical aspects deserve attention. Response to treatment for both plexiform neurofibromas and low-grade gliomas may be gradual, but patients who respond generally show clinical or radiographic improvement within one year of starting treatment.

Most studies have treated patients for two years or more for plexiform neurofibromas or low-grade gliomas. Importantly, plexiform neurofibroma growth often resumes after treatment is stopped, while response appears more durable in low-grade gliomas after treatment suspension.

MEK inhibitors are generally well-tolerated with regular screening and management of side effects. Treatment should be temporarily stopped for clinically significant side effects and can be restarted at a lower dose once the toxicity improves. However, long-term safety data is still being evaluated through ongoing studies and clinical experience.

Consensus Recommendations

An international, multidisciplinary panel of experts developed evidence-driven consensus recommendations for MEK inhibitor use in NF1:

Tumor Manifestations

• MEK inhibitors are approved for the treatment of symptomatic, inoperable plexiform neurofibromas in children; their use in asymptomatic, growing, inoperable plexiform neurofibromas may be appropriate based on the clinical situation
• There is no evidence that monotherapy with MEK inhibitors will prevent or successfully treat malignant peripheral nerve sheath tumors
• MEK inhibitors are effective in treating NF1-associated low-grade gliomas but are best used in the context of a clinical trial or for relapsed disease since their effect on functional outcomes and long-term tumor control are unknown

Non-Tumor Manifestations

• Little clinical data are available for the impact of MEK inhibitors on bony manifestations of NF1 and careful monitoring of skeletal manifestations during treatment and in future clinical trials is recommended
• Plexiform neurofibroma-associated pain may be a potential indication for MEK inhibitor treatment but should be monitored systematically with validated pain measures
• Based on current data, there is no evidence of neurotoxicity with MEK inhibitor treatment in children and young adults; further studies are needed to evaluate any potential neurocognitive benefit

Practical Treatment Issues

• Plexiform neurofibromas and low-grade gliomas response may be gradual, but patients that respond to MEK inhibitors generally show clinical or radiographic response within 1 year
• Most studies have treated for 2 years or more for plexiform neurofibromas or low-grade gliomas; plexiform neurofibroma growth often resumes after treatment is suspended, but response may be more durable in low-grade gliomas
• MEK inhibitors are overall well tolerated with regular screening and management of toxicities but should be held for clinically significant toxicities and can be restarted at a lower dose once the toxicity improves; long-term safety is still being evaluated

Source Information

Original Article Title: MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus

Authors: Peter M. K. de Blank, Andrea M. Gross, Srivandana Akshintala, Jaishri O. Blakeley, Gideon Bollag, Ashley Cannon, Eva Dombi, Jason Fangusaro, Bruce D. Gelb, Darren Hargrave, AeRang Kim, Laura J. Klesse, Mignon Loh, Staci Martin, Christopher Moertel, Roger Packer, Jonathan M. Payne, Katherine A. Rauen, Jonathan J. Rios, Nathan Robison, Elizabeth K. Schorry, Kevin Shannon, David A. Stevenson, Elliot Stieglitz, Nicole J. Ullrich, Karin S. Walsh, Brian D. Weiss, Pamela L. Wolters, Kaleb Yohay, Marielle E. Yohe, Brigitte C. Widemann, and Michael J. Fisher

Publication: Neuro-Oncology, Volume 24, Issue 11, November 2022, Pages 1845–1856

Note: This patient-friendly article is based on peer-reviewed research and aims to accurately represent the original scientific content while making it accessible to patients and caregivers.