Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study

Abstract

Introduction Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. Methods We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. Results Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. Conclusions In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Case report: complete long-lasting response to multimodal third line treatment with neurosurgical resection, carmustine wafer implantation and dabrafenib plus trametinib in a BRAFV600E mutated high-grade glioma

“…Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have yet shown promising results in other cancers refractory to conventional chemotherapy ( 26 ). The safety and effectiveness of MEKi treatment have also been established in improving symptomatology and quality of life in patients affected by plexiform neurofibromas in Neurofibromatosis Type I ( 7 ). Considering brain tumors, MAPK inhibitors have shown encouraging results in LGG showing alterations of this pathway.…”

“…MAPK (mitogen-activated protein kinase) pathway, implicated in carcinogenesis, has been found altered in most glial tumors ( 7 , 8 ), promoting cellular overgrowth and overcoming metabolic stress ( 9 ). The pathway includes a small G protein (RAS) and three protein kinases in a downstream signaling pathway (respectively RAF – composed of A-RAF, B-RAF and RAF-1 or C-RAF kinases, MEK – composed of MEK1 and MEK2, ERK – composed of ERK1 and ERK2) ( 10 , 11 ).…”

“…The BRAF inhibitors vemurafenib, dabrafenib and encorafenib selectively target BRAF kinase, interfering with MAPK signaling pathway ( 16 ). Selumetinib and trametinib are MEK inhibitors (MEKi) ( 7 ). The combination of BRAF and MEK inhibitor have been approved in various cancers by the US Food and Drugs Administration (FDA) ( 17 ) and the European Medicines Agency (EMA).…”

Treatment With Selumetinib for Café-au-Lait Macules and Plexiform Neurofibroma in Pediatric Patients With Neurofibromatosis Type 1

“…The US approved the MEK1/2 inhibitor (MEKi) selumetinib as a treatment option for PN in 2020 owing to substantial reported clinical benefits, including tumor volume reductions and QoL improvements. [2][3][4][5] Selumetinib is currently recommended for patients aged 3 to 18 years with symptomatic, inoperable PN, and it was approved in China in September 2023. This report describes the experiences of 4 patients with PN who underwent prelaunch compassionate use treatment between March 2022 and June 2023.…”

“…Surgery has long been the primary treatment option for patients affected by PN, but its efficacy tends to be limited given high rates of recurrence and adverse effects. The US approved the MEK1/2 inhibitor (MEKi) selumetinib as a treatment option for PN in 2020 owing to substantial reported clinical benefits, including tumor volume reductions and QoL improvements . Selumetinib is currently recommended for patients aged 3 to 18 years with symptomatic, inoperable PN, and it was approved in China in September 2023.…”