Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience

Abstract

MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N = 11) or highgrade CNS tumors (N = 3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N = 9) or in combination (N = 5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with lowgrade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinasedriven CNS tumors. Our observations need to be confirmed in a clinical trial setting.

Response to trametinib treatment in progressive pediatric low-grade glioma patients

“…Comparable to these findings, dose limiting adverse events were seen in 6/18 patients (33%), prompting repetitive treatment interruptions, and termination of treatment in 2/18 patients (11%). Similar rates of trametinib discontinuation due to toxicity have been reported in pediatric patients by Paul et al [24]. We therefore conclude that some individual patients may display an unacceptable toxicity profile, in particular skin toxicity, underscoring the need for early and thorough dermatologist support in trametenib-treated children.…”

“…We could not detect a correlation between dose reduction and response to therapy. This was also not reported in other case series on trametinib treatment of pLGG [21,22,24]. However, a correlation between dose reduction and change in response to therapy needs to be investigated by prospective trials.…”

“…Selumetinib was shown to be active in different genetic backgrounds including KIAA1549:BRAF fusions, BRAF V600E mutation and NF1 mutations in clinical phase 1 and 2 trials [ 17 , 18 ]. However, activity of trametinib in pLGG has only been described in small retrospective case series and case reports [ 21 – 24 , 31 ]. We here report on 18 patients with KIAA1549:BRAF-, BRAF V600E-, FGFR1- or NF1-driven progressive pLGG treated with the MEKi trametinib between 2015 and 2019.…”

“…Two case series reported on two and six progressive PA patients with KIAA1549:BRAF-fusion [21,23], with two partial responses (PR) in one study [23], and two partial responses (PR), three minor responses (MR) and one progressive disease (PD) in the second [21]. The third case series [24] reports on 14 low-and high-grade pediatric MAPK-altered brain tumors of different histologies (11 low-grade and 3 high-grade tumors) treated with trametinib alone or in combination. Eight of the 11 patients with low-grade tumors received trametinib monotherapy, of which four had a BRAF-fusion, one had a BRAF V600E mutation, one an NF1 alteration and two no detected MAPK alteration.…”

“…Trametinib is currently being tested in phase I/II clinical trials (NCT02124772) and first limited data is available in abstract format for patients with BRAF fusions [ 20 ]. The published data on the activity of trametinib in pLGG is derived from case series [ 21 – 24 ]. Two case series reported on two and six progressive PA patients with KIAA1549:BRAF -fusion [ 21 , 23 ], with two partial responses (PR) in one study [ 23 ], and two partial responses (PR), three minor responses (MR) and one progressive disease (PD) in the second [ 21 ].…”