Efficacy Endpoint Standardization in Adult Primary CNS Tumor Trials: Integrating Regulatory Science and Clinical Perspectives in the RANO 2.0 Era

Background/Objectives: Efficacy endpoint selection in adult primary central nervous system (CNS) tumor trials remains challenging because conventional solid tumor frameworks do not adequately capture the anatomical, radiographic, and biological complexity of brain tumors. In particular, postoperative irregular residual lesions, non-enhancing tumor components, and treatment-related imaging changes complicate the interpretation of objective response and progression. This narrative review examines the current landscape of endpoint selection in adult primary CNS tumor trials and discusses strategies for standardization in the Response Assessment in Neuro-Oncology (RANO) 2.0 era from integrated regulatory science and clinical perspectives. Methods: This study was conducted as a narrative review intended to provide a regulatory science-oriented synthesis of efficacy endpoint evaluation in adult primary CNS tumor trials. The literature search primarily utilized PubMed and ClinicalTrials.gov, supplemented by major consensus guidelines, pivotal clinical trials, and regulatory documents from the major regulatory authorities, including those in the United States, Europe, and Japan, published over the past two decades. Search terms included combinations of keywords such as “brain tumor,” “glioblastoma,” “meningioma,” “Phase I,” “Phase II,” “efficacy endpoint,” and “RANO”. In addition to the literature synthesis, this review incorporates findings from our previously published empirical analyses regarding endpoint selection in Phase II glioblastoma trials, Phase II meningioma trials, and Phase I brain tumor trials. Results: Response Evaluation Criteria in Solid Tumors-based response assessment remains fundamentally limited in neuro-oncology. Across recent early-phase trials, substantial heterogeneity persists in endpoint selection and in the operational definitions of objective response rate, progression-free survival, and progression. RANO 2.0 is intended to provide a more unified and implementation-oriented framework by refining baseline definition, progression confirmation, non-enhancing lesion interpretation, and the role of minor response, while improving compatibility with contemporary molecular classification and immunotherapy-era trial design. However, important implementation challenges remain, including potential reproducibility concerns in complex imaging assessments, operational complexity, imaging standardization, and the need for independent central review. Conclusions: Standardization of endpoint strategies in adult primary CNS tumor trials should move beyond simple adoption of conventional solid tumor metrics toward a disease-specific, harmonized framework integrating imaging, clinical context, tumor biology, and regulatory interpretability. This review provides a regulatory science-oriented synthesis linking response assessment criteria, early-phase adult primary CNS tumor trial endpoint trends, empirical analyses, and emerging endpoint frameworks. RANO 2.0 represents an important step toward this goal, but it should be regarded as an evolving framework that requires continued validation, international collaboration, and implementation-focused refinement.