HGG-42. Combined Preclinical and Clinical Investigation of Which Pediatric High-Grade Glioma Subtypes Benefit From Ccnu/Temozolomide

Abstract BACKGROUND The only chemotherapy regimen that has shown a clear survival benefit in pediatric high-grade glioma (pHGG) is combining temozolomide (TMZ) and lomustine (CCNU) with RT per COG ACNS0423. However, which pHGG subgroups benefit from this treatment is unknown. METHODS Through the Children’s Brain Tumor Network (CBTN) database, we found 20 pHGG patients treated with RT-TMZ-CCNU, along with 95 control patients who received other treatment. We compared overall (OS) and event-free survival (EFS) using the Log-rank test for the respective pHGG subtype. We used a patient-derived xenograft (PDX) model, representing newly diagnosed hemispheric pHGG (diffuse hemispheric glioma, G34R-mutant (DHG), to test the effects of combining TMZ-CCNU. RESULTS From our clinical (CBTN) data, we found that median OS for the RT-TMZ-CCNU group was significantly greater compared to the control cohort (990 days (d) vs. 427d, p=0.011), as was EFS (510 vs. 215d, p=0.0041). For patients with hemispheric tumors, median OS and EFS were significantly increased for the RT-TMZ-CCNU group (n=8) vs. controls (n=47) (OS 5,274 vs. 496d, p=0.018; EFS 903 vs. 271d, p=0.018). For patients with midline pHGG, median OS and EFS were not significantly different between the RT-TMZ-CCNU group (n=11) and controls (n=43). In our PDX model, we found that TMZ-CCNU led to long-term survival compared to vehicle control and single-agent treatment (p0.001). DISCUSSION: Patients with hemispheric pHGG had a significant survival benefit from RT-TMZ-CCNU treatment, while those with midline pHGG did not. Hemispheric pHGG, which are enriched for H3G34 and IDH mutations, may be more likely to respond to RT-TMZ-CCNU. These findings are supported by preclinical data showing that mice with DHG, G34R-mutant were cured after TMZ-CCNU treatment. Given our results and those from ACNS0423, RT-TMZ-CCNU should be strongly considered for treatment of patients with hemispheric pHGG and as a backbone for future clinical trials in this population.