BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of 
childhood. Although overall survival is good, disease often recurs. No single 
universally accepted treatment exists for these patients; however, standard 
cytotoxic chemotherapies are generally used. We aimed to assess the activity of 
selumetinib, a MEK1/2 inhibitor, in these patients.
METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 
study in patients with paediatric low-grade glioma in 11 hospitals in the USA. 
Patients aged 3-21 years with a Lansky or Karnofsky performance score greater 
than 60 and the presence of recurrent, refractory, or progressive paediatric 
low-grade glioma after at least one standard therapy were eligible for 
inclusion. Patients were assigned to six unique strata according to histology, 
tumour location, NF1 status, and BRAF aberration status; herein, we report the 
results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I 
pilocytic astrocytoma harbouring either one of the two most common BRAF 
aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). 
Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated 
paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as 
capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 
28-day courses for up to 26 courses. The primary endpoint was the proportion of 
patients with a stratum-specific objective response (partial response or 
complete response), as assessed by the local site and sustained for at least 8 
weeks. All responses were reviewed centrally. All eligible patients who 
initiated treatment were evaluable for the activity and toxicity analyses. 
Although the trial is ongoing in other strata, enrolment and planned follow-up 
is complete for strata 1 and 3. This trial is registered with 
ClinicalTrials.gov, number NCT01089101.
FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable 
patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 
25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine 
(36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The 
median follow-up for the 11 patients who had not had a progression event by Aug 
9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 
25 patients achieved a sustained partial response; median follow-up was 48·60 
months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 
9, 2018. The most frequent grade 3 or worse adverse events were elevated 
creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No 
treatment-realted deaths were reported.
INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive 
pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated 
paediatric low-grade glioma. These results show that selumetinib could be an 
alternative to standard chemotherapy for these subgroups of patients, and have 
directly led to the development of two Children's Oncology Group phase 3 studies 
comparing standard chemotherapy to selumetinib in patients with newly diagnosed 
paediatric low-grade glioma both with and without NF1.
FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the 
American Lebanese Syrian Associated Charities, and AstraZeneca.