Neuropsychological impact of trametinib in pediatric low‐grade glioma: A case series

Abstract

Clinical trials of MEK inhibitors are underway in pediatric low-grade glioma (PLGG) with BRAF oncogene mutations and recurrent/refractory disease. Cognitive and behavioral impacts of MEK inhibitors, such as trametinib, are unknown as these outcomes have not yet been studied. This case series compared cognition and behavior in eight PLGG cases prior to and while on treatment with trametinib compared to four PLGG controls. Intelligence in the trametinib cases was mainly unchanged while on treatment, with mild decline in one of seven cases with complete data. Parent-reported depression symptoms increased in five of eight trametinib cases relative to one of four controls.

Efficacy and Safety of Trametinib in Neurofibromatosis Type 1-Associated Plexiform Neurofibroma and Low-Grade Glioma: A Systematic Review and Meta-Analysis

“…The search strategy initially retrieved 163 potentially relevant clinical studies. A total of eight studies published between 2018 and 2021 were included [25,[32][33][34][35][36][37][38]. None of the studies were randomized controlled.…”

“…The general characteristics and quality assessments of studies included in the meta-analysis are presented in Table 1. Two studies were phase I clinical trials [35,37], and six studies were retrospective case series [25,[32][33][34]36,38]. The eight studies included 127 patients in total.…”

“…Although effective, both regimens are associated with grade three and four toxicities such as secondary malignancy and infertility. In addition, the long-term efficacy is still controversial, with the 5-year progression rate reaching 30% [25,26].…”

“…Trametinib (GSK 1120212) is a MEK1/2 inhibitor that could limit the abnormal activation of the RAS pathway by inactivating the MAPK kinase (MEK), and it is historically used to treat BRAF-mutant melanoma and non-small-cell lung cancer [29,30]. There is one ongoing phase II trial investigating the benefit of trametinib for treating LGGs and pNFs in NF1 individuals [31], and other reports on trametinib for treating NF1-related nervous system tumors have also been published in recent years [25,[32][33][34][35][36][37][38][39][40]. However, due to the mixed inclusion criteria, and the limited sample size, the strength of the evidence remains open to question.…”

Pediatric low-grade glioma: Targeted therapeutics and clinical trials in the molecular era

“…The use of MEK inhibitors in the treatment of NF1-associated plexiform neurofibromas has further informed the management of toxicities in patients with pLGG as these studies have a longer history and have also aimed to capture late effects of MEK inhibitors [70] . Although the management and surveillance of the toxicities of targeted therapies has improved as clinicians have increased experience with the agents, there remains unanswered questions about the long-term impact of these agents on growth and development, including neuropsychological outcomes in children [71 , 72] . Furthermore, follow-up remains short for many studies of targeted therapies, including BRAF, MEK, and mTOR inhibitors, in pediatric patients [46 , 55 , 73] .…”