P17.08.B STANDARDIZING EFFICACY ENDPOINTS IN NEURO-ONCOLOGY TRIALS: A REGULATORY SCIENCE ANALYSIS BASED ON GLIOBLASTOMA PHASE II DESIGNS

Abstract BACKGROUND In solid tumor trials, objective response rate (ORR) defined by RECIST has traditionally served as the primary efficacy endpoint. However, in neuro-oncology, the reliability of ORR is compromised by pseudoprogression, non-enhancing lesions, and glioma-specific imaging complexities. With the publication of RANO 2.0 and the updated WHO CNS classification, there is an urgent need to reassess and harmonize endpoint strategies. From a regulatory science perspective—focusing on the optimization of trial design and evaluation—this study investigates evolving trends in glioblastoma (GBM) phase II trials. MATERIALS AND METHODS We systematically searched Cortellis™ Clinical Trial Intelligence for interventional GBM phase II trials initiated between FY2020 and FY2022. Among 116 identified, 88 trials met inclusion criteria. Primary and secondary efficacy endpoints, study phase, and design features were extracted and compared with trials initiated in FY2017-2019. Fisher’s exact and Wilcoxon rank-sum tests were applied (p < 0.05). RESULTS A total of 101 primary endpoints (PEs) were extracted from 88 trials. Progression-free survival (PFS, 22%), overall survival (OS, 20%), and PFS rate (17%) were the most frequently selected PEs. Time-to-event (TTE) endpoints were used in 73% of trials. ORR was chosen as a PE in only 8% of trials—a significant reduction from 20% in FY2017-2019 (p = 0.022). Across 299 secondary endpoints, ORR appeared in 11%. Notably, 32% of trials employed multiple PEs, and 99% incorporated more than one efficacy endpoint. Subgroup analysis revealed higher ORR use in recurrent GBM and open-label trials. CONCLUSION This regulatory science-based analysis highlights a notable shift away from ORR and toward TTE-based efficacy endpoints in GBM phase II trials, suggesting early methodological convergence with the principles later formalized in RANO 2.0. These trends reflect increasing recognition of the limitations of conventional response metrics and a growing demand for clinically meaningful, reproducible endpoints in early-phase trials for CNS tumors. As RANO 2.0 becomes more widely adopted, future trials should assess its real-world impact on endpoint selection, trial design, and regulatory evaluation. While this study focuses on glioblastoma, the findings may also inform future discussions on harmonized endpoint strategies across CNS tumor types and potentially beyond, including other neurological indications.