An evaluation of selumetinib for the treatment of neurofibromatosis type 1-associated symptomatic, inoperable plexiform neurofibromas

ABSTRACT

Introduction: Plexiform neurofibromas (PNs) are present in up to half of patients with neurofibromatosis type 1 (NF1). PNs consist of a proliferation of abnormal cells in the nerve sheath and can lead to significant comorbidities. Most PNs are diagnosed in early childhood when the most rapid growth rate generally occurs. Historically there has been a paucity of effective treatment options for patients with PNs, with surgery being the standard of care. As knowledge has increased regarding the NF1 gene and the function of its protein product neurofibromin, therapies targeting the Ras signaling pathway have been tested, first in preclinical models and subsequently in clinical trials.

Areas covered: This review focuses on selumetinib (KOSELUGO^TM; AZD6244, ARRY-142,886) and the management of PNs. A literature search was undertaken using PubMed with keywords ‘neurofibromatosis,’ ‘plexiform neurofibromas,’ ‘selumetinib,’ and ‘MEK inhibitor.’

Expert opinion: Selumetinib is the first FDA approved drug for the treatment of PNs. Prior to its development, options for patients with PNs causing morbidity were limited. Surgical intervention can be difficult, debilitating, and often futile. With the efficacy seen in the phase 1 and 2 trials for patients with NF1-associated PNs, the outlook has become one of the hope and excitement.

KEYWORDS:

• Koselugo
• mek inhibitor
• MEK-ERK pathway
• neurofibromatosis
• plexiform neurofibroma
• rasopathy
• selumetinib

Article highlights

• Neurofibromatosis type 1 is a common genetic tumor predisposition syndrome affecting 1 in 3,000 people.

• Loss-of-function alterations in the NF1 gene cause decreases in functional neurofibromin, which subsequently leads to activation of the MEK-ERK pathway.

• Plexiform neurofibromas are one of the most common tumors in patients with NF1.

• Selumetinib is a MEK inhibitor that has shown efficacy in the treatment of plexiform neurofibromas.

• Selumetinib is the first drug with FDA-approval for the treatment of children aged 2 years and older with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas.

Acknowledgments

AstraZeneca provided a scientific accuracy review at the request of the journal editor.

Declaration of interest

Prior to the manuscript’s acceptance, Laura Metrock attended an advisory board for Astra Zeneca (Considerations for Treatment of NF1 Plexiform Neurofibromas Advisory Board) and was compensated for her time. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.