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Background: Chemoradiation(CRT)with temozolomide(TMZ/RT→TMZ)is the standard of care for newly diagnosed GBM.This trial determined if the addition of Bev to standard CRT improves survival(OS)or progression-free survival(PFS)in newly diagnosed GBM.Methods: This phase Ⅲ trial was conducted by the RTOG,NCCTG,and ECOG.Neurologically stable pts > 18 yrs with KPS ≥ 60,and > 1cm3 tumor tissue block,were randomized to Arm 1: standard CRT + placebo or Arm 2: standard CRT plus Bev(10 mg/kg iv q 2wks).Experimental treatment began at wk 4 of radiation then thru 6-12 cycles of maintenance chemotherapy.Protocol specified co-primary endpoints were OS and PFS,with significance levels of.023 and.002,respectively.At progression,treatment was unblinded and pts allowed to crossover or continue Bev.Symptom,QOL and neurocognitive(NCF)testing was performed in the majority of pts.Secondary analyses evaluated impact of MGMT methylation(meth)and prognostic 9 gene signature status.Results: From 978 registered pts,637 were randomized.Inadequate tissue(n=105)and blood on imaging(n=40)were key reasons for non-randomization.No difference was found between arms for OS(median 16.1 vs.15.7 mo,p = 0.11).PFS was extended for Arm 2(7.3 vs.10.7 mo,p = 0.004).Pts with MGMT meth had superior OS(23.2 vs.14.3 mo,p < 0.001)and PFS(14.1 vs.8.2 mo,p < 0.001).Neither the 9 gene signature nor MGMT predicted selective benefit for Bev treatment,but best prognosis pts(MGMT meth,favorable 9-gene),had a worse survival trend with Bev(15.7 vs 25 mo p = 0.08).To date,128 pts were unblinded on Arm 1(salvage Bev in 86)and 87 pts on Arm 2(continued Bev in 39).Increased grade ≥ 3 toxicity was seen with Bev,mostly neutropenia,hypertension,and DVT/PE.Conclusions: The addition of Bev for newly diagnosed GBM did not improve OS,did improve PFS but did not reach the significance criterion.MGMT and 9 gene profile did not identify selective benefit,but risk subset results suggested strongly against the upfront use of Bev in the best prognosis pts.Full interpretation of the PFS results incorporating symptom burden,QOL,and NCF is ongoing.Support: NCI U10 CA 21661,U10 CA37422,and Genentech.