Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

Abstract

Neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PN) are peripheral nerve sheath tumors that can significantly affect the quality of life. Until recently, surgery was the only treatment for these tumors. However, in most cases, surgery cannot achieve complete tumor removal and carries a high risk of postoperative deficits. Therefore, the recent approval of the MEK inhibitor selumetinib for the treatment of NF1-associated PN provides a long-awaited novel therapeutic option. Here, we report our experience with MEK inhibitor treatment in 12 pediatric NF1 patients with inoperable symptomatic PN. Eight patients received trametinib (median therapy duration 12.13 months and range 4–29 months), and four patients received selumetinib (median therapy duration 6.25 months and range 4–11 months). Volumetric magnetic resonance imaging (MRI) after 6 months of treatment was available for seven trametinib patients (median tumor volume reduction of 26.5% and range 11.3–55.7%) and two selumetinib patients (21.3% tumor volume reduction in one patient and +3% tumor volume change in the other one). All patients reported clinical benefits such as improved range of motion or reduced disfigurement. Therapy-related adverse events occurred in 58.3% of patients and mainly consisted of skin toxicity, paronychia, and gastrointestinal symptoms. Two patients discontinued trametinib treatment after 14 and 29 months when severe skin toxicity occurred and no further reduction of tumor size was observed. In one patient, discontinuation of therapy resulted in a 27.2% tumor volume increase as demonstrated on volumetric MRI 6 months later. Our data show that MEK inhibition is a novel therapeutic approach for inoperable PN with promising results and a manageable safety profile.

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real‐world case series

“…reported a median response volume change of only −27.9% (range of −55.1 to 2.2) despite clear symptomatic and functional benefits; no correlation between clinical improvement and tumour volume change was found 7 . Three case series reported tumour shrinkage in 47%–94% of patients, with symptom improvement in 78%–100% 12–14 . We found that most had symptom improvement, especially pain.…”

“…In one series, four patients developed asymptomatic left ventricular systolic dysfunction; only one required therapy cessation 14 . No other cardiac, ophthalmological or pulmonary events have been reported in case series 12–14 . We described reversible toxicities following medication holds and/or dose reductions.…”

“…7 Three case series reported tumour shrinkage in 47%-94% of patients, with symptom improvement in 78%-100%. [12][13][14] We found that most had symptom improvement,…”

“…14 No other cardiac, ophthalmological or pulmonary events have been reported in case series. [12][13][14] We described reversible toxicities following medication holds and/or dose reductions. Of the rarer events, oedema has been reported in children on selumetinib.…”

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies

“…MEK inhibitors are targeted agents that inhibit the mitogen‐activated protein kinase kinase (MAPK) enzymes involved in cell growth and proliferation. Several MEK inhibitors are approved for use in cancer and neurofibromatosis 1 48‐50 . Mutations in the RAS/MAPK pathway, namely mutations in MAP2K1 and KRAS , have been implicated in extracranial AVMs 51‐59 .…”