Prospective phase II clinical trial of molecular glioblastoma (historical grade 2 and 3 IDH wildtype gliomas) preliminary novel exploratory analyses: Treatment intensification, margin reduction and epigenetic stratified outcomes with radiation therapy and chemotherapy

Purpose: Molecular glioblastoma (molGBM) is a variant lacking the full histopathological profile of glioblastoma. We report a trial aimed at addressing the optimal management of this newly recognized rarer form of glioma. Methods: In this phase II study, molGBM patients were treated with radiation to a dose of 60Gy to the gross tumor volume (GTV) only, and a single smaller margin potentially as low as 1cm to the clinical tumor volume (CTV). As the trial is ongoing, we report on important exploratory biomarker findings correlating with median overall survival (mOS). Analysis included Kaplan-Meier and univariable/multivariable cox proportional hazard models. Available pre-operative tissue was subjected to epigenetic/DNA methylation profiling on the Infinium EPIC platform. Results: From 2019 to 2023, 25 patients were enrolled based on initial pathology review, with 23 identified on 2nd review as grade 2 and 3 disease. 74% of patients received concurrent chemoradiotherapy with adjuvant chemotherapy. Of 9 patients with profiling, 5 were classified as mesenchymal subtype, while 4 matched to a variety of other phenotypes, including a novel F type GBM. Despite similar histological appearance corresponding to “lower grade glioma”, molGBM classified as IDH-wildtype mesenchymal had mOS of 15.7 months (95% CI 15.5-NA) while the other tumors had a mOS of 37.7 months (95% CI 10.9-NA). Conclusion: Our results demonstrate underlying heterogeneity within the molGBM population, pointing to future hypothesis-generating risk stratification strategies. We also demonstrate the feasibility of CTV reduction with therapy intensification to set a practice standard for RT management of non-enhancing molGBM.