Co-expression of ERBB2 and ERBB4, reported in 75% of pediatric
ependymomas, correlates with worse overall survival.
Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with
ependymoma in a phase I study.
Bevacizumab exposure in
ependymoma xenografts leads to ablation of
tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of
bevacizumab and
lapatinib in children with recurrent
ependymomas. Patients ≤ 21 years of age with recurrent
ependymoma received
lapatinib orally twice daily (900 mg/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/dose) and
bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course.
Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of
bevacizumab and 24-48 h following dose 2 of
bevacizumab. Twenty-four patients with a median age of 10 years (range 2-21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had
anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥ 4 courses (range 4-14). Grade 3 toxicities included
rash, elevated ALT, and
diarrhea. Grade 4 toxicities included peri-
tracheostomy hemorrhage (n = 1) and elevated
creatinine phosphokinase (n = 1). The median
lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of
bevacizumab and
lapatinib was well tolerated in children with recurrent
ependymoma, it proved ineffective.