Abstract
While Response Assessment in Neuro-oncology (RANO) criteria remain the standard for brain tumor evaluation, 3D volumetric measurements may provide more accurate tumor assessments. We compared 2D RANO per blinded independent review committee (BIRC) with 3D volumetric RANO to evaluate correlation, progression detection and clinical outcomes in patients with mIDH1/2 diffuse glioma from INDIGO (NCT04164901). Data comparing vorasidenib (n=168) with placebo (n=163) were analyzed. Per RANO criteria for low-grade gliomas, analyses of 2D versus 3D volumetric progression-free survival (PFS) by BIRC, correlation between measurements, time to next intervention (TTNI), and response concordance were performed. Mixed models evaluated longitudinal correlation; weighted kappa statistics assessed agreement in response categorization. Strong positive correlation was observed between 2D and 3D measurements (Pearson, r=0.858; mixed model, r=0.861). 3D volumetric assessment demonstrated a stronger treatment effect (HR 0.24; 95% CI 0.15, 0.37) than 2D assessment (HR 0.35; 95% CI 0.25, 0.49). 3D volumetric assessment detected fewer progression events (vorasidenib, 16.1%; placebo, 44.2%) than 2D assessment (vorasidenib, 32.1%; placebo, 63.8%). Importantly, 3D volumetric PFS visually matched TTNI with similar treatment effect sizes. Weighted kappa analysis showed fair agreement between methods for best overall response (0.382) and all timepoint assessments (0.325). However, across all timepoint responses, 2D assessments identified more minor response (MR) and progressive disease (PD) classifications (MR: 2D, n=80; 3D n=54; PD: 2D, n=389; 3D, n=266) while 3D volumetric assessments identified more stable disease classifications (2D, n=1410; 3D, n=1552). 3D volumetric assessments demonstrated stronger treatment effects than 2D assessments, with similar treatment effect sizes for 3D PFS and TTNI. 3D volumetric assessments yielded fewer PD but more SD classifications versus 2D, suggesting a more conservative progression threshold or stable tumor burden measurement over time. Volumetric assessment may provide a more clinically meaningful determination of progression in Grade 2 glioma trials, potentially impacting future trial design and endpoint selection.