FINAL ANALYSIS OF THE HIT-HGG-2007 TRIAL (ISRCTN19852453): SIGNIFICANT SURVIVAL BENEFIT FOR PONTINE AND NON-PONTINE PEDIATRIC HIGH-GRADE GLIOMAS IN COMPARISON TO PREVIOUS HIT-GBM-C/-D TRIALS

Abstract The aim of the HIT-HGG-2007 trial (ISRCTN19852453) was to demonstrate therapeutic non-inferiority of temozolomide radiochemotherapy for pediatric patients (3-18 years) with high-grade gliomas (pedHGG) in comparison to the cisplatinum-based radiochemotherapy of the two previous clinical trials HIT-GBM-C/-D. Between 06/2009 and 12/2016, 456 patients were enrolled at 79 centers in Germany, Austria, and Switzerland (n=18 dropouts, remaining patients for confirmatory analysis: n=438). 438 patients from HIT-GBM-C/-D served as historical control. All pedHGG diagnoses had been confirmed by central neuroradiological and neuropathological review. Primary objective was achieved since non-inferiority of HIT-HGG-2007 in comparison to HIT-GBM-C/-D as indicated by 6 months event-free survival (EFS) was statistically confirmed (p=0.0125). Statistical survival analyses even revealed a better overall survival (OS) and EFS for HIT-HGG-2007 patients in comparison to their HIT-GBM-C/-D counterparts (EFS: p<0.0001; OS: p=0.0328). While EFS subgroup analyses for pontine and non-pontine pedHGG also showed a better survival of HIT-HGG-2007 patients (median EFS pontine pedHGG: 8.2 (n=152; confidence interval (CI): 7.6-9.4) versus 6.2 (n=170; CI: 5.5-6.9) months, p=0.0079; median EFS non-pontine pedHGG: 10.7 (n=276; CI: 9.6-12.4) versus 7.4 (n=267; CI: 6.4-9.2) months, p<0.0001), OS was only improved in HIT-HGG-2007 patients with non-pontine pedHGG (median OS non-pontine pedHGG: 19.3 (CI: 16.8-23.3) versus 16.2 (CI: 14.2-19.1) months; p=0.0181) but not with pontine pedHGG (median OS pontine pedHGG: 11.4 months versus 11.3 months, p=0.4021) Toxicity profile of HIT-HGG-2007 seemed very favorable with most CTCAE (common toxicity criteria adverse event) ≥ grade 3 as hematological toxicity, hepatotoxicity, and neurotoxicity. Less toxicity was observed during concomitant radiochemotherapy in comparison to HIT-GBM-C/-D. Further subgroup survival analyses as well as the assessment of the impact of MGMT promoter methylation are ongoing. In conclusion, our data show non-inferiority of the HIT-HGG-2007 trial with increased survival and less toxicity when compared with previous trials HIT-GBM-C/-D.