From Pages to Practice

By Angela Castellanos, MD

Published July 1, 2020


For many medical students, their first encounter with neurofibromatosis type 1 (NF1) is as one of the many neurocutaneous syndromes to memorize along with the associated skin findings. Often, we learn to identify the café-au-lait macules and axillary freckling of NF1 without understanding plexiform neurofibromas (PNFs), one of the many other clinical manifestations of NF1. These nerve tumors are a significant cause of morbidity in patients with NF1. They can be superficial or deep and spread along fascicles of the affected nerve, becoming entwined and vascularized in the nearby anatomical structures. Because of their varied size and locations, PNFs can be difficult to remove surgically, cause disfigurement and pain, and compress vital organs and the airway.

Currently, no specific medical treatment exists for these tumors, and many are inoperable. Therefore, children with inoperable PNFs need another treatment option. Investigators conducted an open-label phase 2 trial of oral selumetinib, a selective MEK inhibitor that targets the overactive RAS pathway of NF1, in 50 children with NF1 and symptomatic PNFs. They demonstrated clinically meaningful improvements in pain, function, and quality of life in most patients, providing promise of a treatment for this difficult-to-treat manifestation of NF1. Although the benefits of selumetinib are clear in this study, considerable side effects were noted in more than 40% of participants.

The following NEJM Journal Watch summary further explains the study and its findings.


Selumetinib for Children with Inoperable Plexiform Neurofibromas

Roy E. Strowd, MD reviewing Gross AM et al. N Engl J Med 2020 Apr 9

Neurofibromatosis type 1 (NF1) is the most common inherited neurological disorder, affecting 1 in 3000 individuals. Among the many clinical manifestations, plexiform neurofibromas occur in half of patients and result in disfigurement, pain, and neurological dysfunction.

Selumetinib, an oral selective MEK inhibitor, is the first approved agent to target symptomatic plexiform neurofibromas in children with NF1. To assess its effectiveness in this setting, investigators conducted an industry-supported, open-label, phase II study of 50 patients (aged, 3–18 years) who received selumetinib (25 mg/m2) twice daily for up to 2 years.

Results were as follows:

  • 70% of patients had a confirmed partial response (the primary objective); 56% had a response lasting ≥1 year.

  • 68% of patients had improved clinical function, 74% had a clinically meaningful improvement in pain, 48% had improved quality of life, 78% had improved motor strength, and more than half of patients with airway obstruction had significant improvement.

  • The most common adverse reactions, occurring in ≥40% of patients, were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, acne, paronychia, and pruritus.

  • Asymptomatic elevation in creatine phosphokinase was observed.

Selumetinib can also cause cardiomyopathy and ocular toxicity (including retinal vein occlusion, retinal pigment epithelial detachment, and impaired vision), but these were not observed in this trial.

Comment: This landmark study changes practice for clinicians who treat NF1 patients. Selumetinib ushers in a new era of management of these disfiguring tumors that impair function. Ongoing studies are now investigating the activity of selumetinib for other manifestations of NF1, including optic pathway gliomas, and in adult patients with NF1.

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Angela Castellanos is a pediatric hospitalist and podcast producer based in Boston, MA. Her interests include health literacy, health equity, and health information. She was an editorial fellow at NEJM from 2018-2019.