Abstract
BACKGROUND: In the Phase 3 INDIGO trial (NCT04164901), vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), improved progression-free survival (PFS) versus placebo in patients with mIDH1/2 diffuse glioma. While two-dimensional (2D) measurements of tumors remain the standard for clinical trials, tumor volume better captures the true extent of disease and can provide quantitative evaluation of treatment effect through analysis of growth dynamics. We utilized data from the INDIGO trial to evaluate tumor volume as a predictive marker in mIDH1/2 glioma. MATERIAL AND METHODS: PFS was assessed by blinded independent review committee (BIRC) using modified Response Assessment in Neuro-Oncology for low-grade gliomas criteria (2D). Tumor volume was measured using semiautomated segmentation on magnetic resonance imaging scans at baseline and every 12 weeks (3D). Pearson correlation coefficient and mixed-effect models were used to evaluate relationships between 2D and 3D assessments. Cox proportional hazards models were used to analyze associations between baseline tumor volume, tumor growth rate and clinical outcomes, including PFS and time to next intervention (TTNI). RESULTS: Despite more fluctuations and variability in 2D measurements than in 3D measurements over time, there was a strong positive correlation both for individual measurements (R=0.858) and when accounting for repeated measurements within the same patients (R=0.861). While baseline tumor volume appeared prognostic for TTNI, it only trended toward association with PFS by BIRC. Increase in volumetric growth at any time point during treatment increased the risk of progression or death (hazard ratio [HR] 1.061; 95% confidence interval [CI] 1.038, 1.084; P<0.0001) and the risk of next intervention or death (HR 1.059; 95% CI 1.037, 1.082; P<0.0001). Volumetric growth during the first 6 months of treatment was predictive of PFS (HR 1.046; 95% CI 1.026, 1.067; P<0.0001) and TTNI (HR 1.051; 95% CI 1.031, 1.071; P<0.0001) regardless of treatment assignment. CONCLUSION: Using data from the Phase 3 INDIGO trial of patients with mIDH1/2 glioma, we found a high correlation between 2D and 3D assessments. While baseline tumor volume showed variable prognostic value, the substantial association between volumetric growth rate and outcomes suggests that early tumor volume changes can serve as reliable surrogate for both PFS and TTNI. These findings support the inclusion of 3D volumetric assessment in future clinical trials and treatment evaluation of diffuse gliomas. Study sponsored by Servier.