Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma
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CLINICAL STUDY
Trametinib for the treatment of recurrent/progressive pediatric low‑grade glioma Neevika Manoharan1,2 · Jungwhan Choi3 · Christine Chordas1 · Mary Ann Zimmerman1 · Jacqueline Scully1 · Jessica Clymer1 · Mariella Filbin1 · Nicole J. Ullrich1,4 · Pratiti Bandopadhayay1 · Susan N. Chi1 · Kee Kiat Yeo1 Received: 15 June 2020 / Accepted: 7 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG often require numerous treatment modalities including surgery, chemotherapy, rarely radiation therapy and, more recently, molecularly targeted therapy. We describe our institutional experience using the MEK inhibitor, trametinib, for recurrent/progressive pLGGs. Methods We performed a retrospective, IRB-approved, chart review of all pediatric patients treated with trametinib for recurrent/progressive pLGGs at Dana-Farber/Boston Children’s Cancer and Blood Disorder Center between 2016 and 2018. Results Eleven patients were identified, of which 10 were evaluable for response. Median age at commencement of trametinib treatment was 14.7 years (range 7.3–25.9 years). Tumor molecular status included KIAA1549-BRAF fusion (n = 4), NF1 mutation (n = 4), FGFR mutation (n = 1) and CDKN2A loss (n = 1). Median number of prior treatment regimens was 5 (range 1–12). Median duration of treatment with trametinib was 19.2 months (range 3.8–29.8 months). Based on modified RANO criteria, best responses included partial (n = 2), minor response (n = 2) and stable disease (n = 6). Two patients remain on therapy (29.8 and 25.9 months, respectively). The most common toxicities attributable to trametinib were rash, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced significant intracranial hemorrhage (ICH) while on trametinib. While it is unclear whether ICH was directly attributable to trametinib, therapy was discontinued. Conclusion Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation, with particular attention to the potential risk for intracranial hemorrhage. Early phase multi-institutional clinical trials are underway. Keywords Trametinib · MEK inhibitor · Low-grade glioma · Pediatric · MAPK · Central nervous system neoplasms
Introduction
* Kee Kiat Yeo [email protected] 1
Dana‑Farber Cancer Institute, Boston Children’s Cancer and Blood Disorder Center, 450 Brookline Ave, Boston, MA 02215‑5450, USA
2
Kids Cancer Centre, Sydney Children’s Hospital, Sydney, Australia
3
Department of Radiology, Boston Children’s Hospital, Boston, USA
4
Department of Neurology, Boston Children’s Hospital, Boston, USA
Pediatric low-grade gliomas (pLGGs) constitute a heterogenous group of WHO grade I and II tumors, and are the most common central nervous system
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