Response to trametinib treatment in progressive pediatric low-grade glioma patients
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CLINICAL STUDY
Response to trametinib treatment in progressive pediatric low‑grade glioma patients Florian Selt1,2,3 · Cornelis M. van Tilburg1,2,3 · Brigitte Bison4 · Philipp Sievers5,6 · Inga Harting7 · Jonas Ecker1,2,3 · Kristian W. Pajtler1,3,14 · Felix Sahm1,5,6 · Annabelle Bahr8 · Michèle Simon8 · David T. W. Jones1,15 · Lennart Well9 · Victor‑Felix Mautner10 · David Capper11,12 · Pablo Hernáiz Driever8 · Astrid Gnekow13 · Stefan M. Pfister1,3,14 · Olaf Witt1,2,3 · Till Milde1,2,3 Received: 2 August 2020 / Accepted: 29 September 2020 © The Author(s) 2020
Abstract Introduction A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. Methods In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. Results We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Conclusions Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens. Keywords Pediatric low-grade glioma · Targeted therapy · BRAF · NF1 · MAPK pathway · MEK inhibitor · Trametinib
Introduction Low-grade gliomas (pLGG) are the most common brain tumors in children and account for about 30% of all pediatric brain tumors [1, 2]. Standard of care (SOC) treatment options such as surgery, followed by chemotherapy and occasionally radiotherapy (RT) where indicated, have been shown to be effective, leading to 10-year overall survival (OS) and event-free survival (EFS) of 94% and 44%, respectively [3]. Chemotherapy is currently recommended * Till Milde t.milde@kitz‑heidelberg.de Extended author information available on the
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