Vorinostat, temozolomide (TMZ) or bevacizumab (BEV) with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children’s Oncology Group Study

Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly-diagnosed HGG who received maintenance temozolomide and bevacizumab. Patients ≥3 and <22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%) and 59.3% (±9.5%), respectively with no significant difference among treatment arms. Three- and 5-year EFS for the entire cohort was 14.8% and 13.4%, respectively with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (p=0.03), whereas H3.3 K27M mutations (p=0.0045) and alterations in PIK3CA or PTEN (p=0.025) were associated with worse outcomes. Patients with telomerase- and ALT-negative tumors (n=4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (p=0.002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of telomere maintenance mechanism (p=0.0012). Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly-diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.