2048 Background: In GBM, VEGF inhibition decreases vascular permeability and MRI contrast enhancement (CE), which may or may not reflect meaningful anti-tumor activity. We sought to evaluate the relationships between different imaging modalities and anti-tumor activity in a prospective phase II trial of BEV, TMZ and HFSRT in GBM. Methods: Newly diagnosed GBM pts (N=40) received HFSRT with concomitant/ adjuvant BEV and TMZ. All pts underwent dynamic susceptibility contrast MR perfusion (DSC) at baseline, after HFSRT and every 2m. An FDG-PET scan was done at cycle 6. McDonald and RANO response criteria were applied. Results: DSC showed early/progressive decreases in relative cerebral blood volume (rCBV): baseline mean rCBV: 2.77; 6 weeks: 1.65 (p=0.014); 2m: 1.07 (p<0.001); 4m: 0.98 (p<0.001). Conversely, the extent of FLAIR hypersignal progressively increased (mean diameter product: 953, 1165, 1145, 1384 at 6 wks, 2m, 4m and 6m). Response rates per McDonald vs RANO were: complete response (27 vs 10%), partial (63 vs 63%), stable disease (3% vs 20%), progression (7 vs 7%). Because progressive FLAIR occurred within the RT port, time to radiographic progression per McDonald and RANO were identical: median 13m. Residual hypermetabolism seen at the 6m PET (N=6/31) predicted poor survival (p<0.001). Three pts with progressive FLAIR but not CE underwent re-resection; two had true PD and one had mainly radionecrosis. Conclusions: As treatment failure was mostly local, RANO criteria did not shorten time to progression compared to McDonald. DSC depicted early changes in rCBV linked to VEGF modulation, validating DSC as a reliable tool to evaluate anti-VEGF properties of new drugs in vivo. However, VEGF modulation was not predictive of durable anti-tumor activity. A positive PET at 6m predicted poor survival, indicating treatment failure even if other imaging modalities suggested otherwise. However, tumor progression may still be present despite negative PET and DSC, particularly in the setting of increasing non-enhancing FLAIR within the RT port. New imaging tools and improved response criteria are needed to guide management of these pts.