A new targeted therapy has entered the European market for patients with Neurofibromatosis Type 1 (NF1) who develop plexiform neurofibromas (PN). These benign tumors, which form in the supportive tissues of the peripheral nervous system, can cause significant health complications and carry a risk of malignant transformation in a minority of cases.

NF1, also known as von Recklinghausen disease, is a rare genetic disorder affecting approximately 1 in 3,000 individuals. The condition results from inherited or newly developed mutations in the NF1 gene located on chromosome 17, which encodes for the protein neurofibromin. Neurofibromin acts as a negative regulator of the RAS/RAF/MEK/ERK signaling pathway--an essential cascade responsible for controlling cellular proliferation. When neurofibromin is deficient, unchecked cell growth can lead to the formation of plexiform neurofibromas. These tumors often infiltrate nerves in a network-like pattern, making surgical removal complex and sometimes necessitating excision of the affected nerve. In about 8 to 13 percent of cases, these growths can evolve into malignant peripheral nerve sheath tumors.

For patients with symptomatic, inoperable PN, treatment options have expanded with the availability of MEK inhibitors. Previously, Selumetinib was the only approved MEK inhibitor for this indication within the European Union, initially restricted to children aged three and above and adolescents. Recent regulatory changes have broadened its use to include adult patients.

Introduction of Mirdametinib as a New Therapy Option

The latest addition to this therapeutic class is Mirdametinib (marketed as Ezmekly®), available as 1 mg and 2 mg hard capsules and as 1 mg tablets for oral suspension. This medication is indicated for both pediatric and adult patients aged two years and older who present with symptomatic, inoperable plexiform neurofibromas associated with NF1.

Mirdametinib is a selective, non-competitive inhibitor of the MEK1 and MEK2 enzymes, components of the signaling pathway responsible for tumor progression in NF1. The recommended dosage is 2 mg per square meter of body surface area, administered twice daily for the first 21 days of each 28-day treatment cycle. Capsules are to be swallowed whole, while the tablets may be dissolved in water for easier administration. The treatment can be taken with or without food and is to be continued until disease progression or intolerable side effects arise. The prescribing information outlines protocols for dose adjustment or temporary discontinuation in cases of certain adverse reactions before permanent cessation is considered.

Monitoring and Managing Side Effects

While Mirdametinib offers a new hope for affected patients, several potential side effects warrant careful monitoring:

• Ocular Toxicity: Complications such as retinal vein occlusion and detachment of the retinal pigment epithelium have been frequently observed in adults. Regular ophthalmic evaluations are required before and during treatment, and patients should promptly report any new vision disturbances.
• Cardiac Effects: Reductions in left ventricular ejection fraction (LVEF) have been documented in both pediatric and adult populations. Cardiac function should be assessed prior to therapy initiation, then every three months during the first year, and as clinically indicated thereafter.
• Cutaneous Reactions: Common dermatological side effects include acneiform dermatitis, non-acne rashes, dry skin, hair loss, and itching. Early intervention with supportive care, such as moisturizing creams, is advised at the first sign of skin toxicity.

Other frequently reported adverse events encompass gastrointestinal symptoms (diarrhea, nausea, vomiting), elevated creatine phosphokinase, musculoskeletal pain, fatigue, and headaches.

Implications for Clinical Practice

The introduction of Mirdametinib expands the arsenal of targeted therapies for individuals affected by NF1-related plexiform neurofibromas. With the potential to manage previously inoperable tumors and to improve quality of life, the new MEK inhibitor addresses an important unmet medical need. However, its use requires rigorous patient monitoring and adherence to recommended safety protocols, particularly concerning vision, cardiac health, and skin integrity.

Healthcare professionals should remain alert to possible drug interactions, including those with commonly used medications such as diclofenac, and manage therapy on a case-by-case basis to optimize outcomes and minimize risks.

As more data emerges from clinical practice, ongoing evaluation of the long-term safety and efficacy of MEK inhibitors like Mirdametinib will be essential in refining treatment strategies for NF1 patients with complex tumor profiles.