Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor
of childhood. Although overall survival is very good, many children suffer from multiple
progressions and functional morbidities. There is no one universally accepted therapy
for children with recurrent disease, however, standard cytotoxic chemotherapies are
often utilized by most practitioners. The Pediatric Brain Tumor Consortium conducted
a multi-institutional phase II study evaluating selumetinib (AZD6244, ARRY-142886),
a MAP/ERK Kinase I/II inhibitor, in patients with recurrent, refractory or progressive
pLGG assigned to numerous strata. The aim of the study was to evaluate the efficacy
of selumetinib in these patients. Eligibility required age 3–21 y/o, a Lansky or Karnofsky
performance score greater than 60 and the presence of recurrent, refractory or progressive
pLGG after at least one standard therapy. Stratum 1 included children with World Health
Organization (WHO) grade I pilocytic astrocytoma (PA) harboring either one of the
two most common BRAF aberrations ( KIAA1549-BRAF fusion or the BRAF V600E mutation).
Stratum 3 included children with any neurofibromatosis type 1 (NF1)-associated pLGG
(WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended
phase II dose of 25 mg/m 2 twice daily. The primary endpoint was stratum-specific
objective response rate assessd by the local site and sustained for at least 8 weeks.
All responses were reviewed centrally and statistical analyses were done as per protocol.
Although the trial ( NCT01089101 ) is still ongoing in other strata, enrollment and
planned follow-up is compete on both strata 1 and 3. Between July 25, 2013, and June
12, 2015, 25 eligible and evaluable children were accrued to stratum 1, and between
August 28, 2013, and June 25, 2015, 25 eligible and evaluable children were accrued
to stratum 3. On stratum 1, 9/25 (36%) patients achieved a partial response (PR).
The median follow-up for the 11 patients who have not yet experienced an event is
36.4 months (4.4–50.5; IQR=23.9). On stratum 3, 10/25 (40%) patients achieved a PR
with a median follow-up of 48.6 months (8.6–59.1; IQR=12.2) for the 17 subjects without
progressions. All patients evaluable for visual acuity had improved or stable vision.
The most common attributable toxicities on both strata were grade 1 and 2 CPK elevation,
hypoalbuminemia, dyspnea, rash, duodenal ulcer, anemia, dry skin, fatigue and diarrhea.
Rare grade 3 toxicities included elevated CPK (n=5), maculopapular rash (n=5), neutropenia
(n=3), nausea (n=3), paronychia (n=3), acneiform rash (n=2), diarrhea (n=2), elevated
ALT (n=1), decreased ejection fraction (n=1), gastric hemorrhage (n=1), headache (n=1),
skin infection (n=1), tooth infection (n=1) and weight gain (n=1). There was only
one grade 4 toxicity, lymphopenia. There were no treatment-realted deaths. Patient
reported outcomes and quality of life assessments were not part of the current study.
Selumetinib is active against recurrent, refractory or progressive PA harboring common
BRAF aberrations and NF1-associated pLGG. To our knowledge, this is one of the first
prospectively tested and successful molecularly-targeted agents in pLGG. These data
not only provide an alternative to standard chemotherapy for these subgroups of patients,
but this success has led to an interest in exploring efficacy in patients as a first-line
therapy. In fact, these data have directly led to the development of two Children’s
Oncology Group phase III studies in newly diagnosed pLGG patients both with and without
NF1 comparing standard chemotherapy to selumetinib. The current trial was funded by
a National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) PBTC U01
Grant: 2UM1CA081457 (UM1) and by the American Lebanese Syrian Associated Charities.