Neurocognitive Function (NCF) Substudy and Mini-Mental State Examination (MMSE) Results from the Randomized, Placebo-Controlled Phase III AVAglio Trial of Bevacizumab (BEV) Added to Radiotherapy (RT) and Temozolomide (TMZ) for Newly Diagnosed Glioblastoma (S22.002)

OBJECTIVE: To determine the impact of BEV added to RT/TMZ on NCF in patients enrolled in AVAglio. BACKGROUND: Neurocognitive impairment is common in glioblastoma and correlates with decreased functional independence. BEV+RT/TMZ achieved a statistically significant improvement in PFS versus placebo (Plb)+RT/TMZ (co-primary endpoint). Longitudinal MMSE results and an NCF substudy are presented. DESIGN/METHODS: Patients 蠅18 years with histologically confirmed glioblastoma received: RT/TMZ plus BEV or Plb (6wks); a 28-day treatment break; BEV or Plb with TMZ (6 cycles); BEV or Plb until progression/unacceptable toxicity. MMSE was evaluated at each disease assessment (exploratory endpoint). The NCF substudy (three validated neuropsychological tests) comprised: Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), Controlled Oral Word Association (COWA). RESULTS: All patients participated in MMSE evaluation (458 BEV+RT/TMZ; 463 Plb+RT/TMZ) at baseline. Completion rates (both arms): 83-94% up to 70wks after baseline; 57-62% at the time of progression. Mean change from baseline was similar between arms at each timepoint. Based on the Reliable Change Index (RCI), 蠅80% of patients were stable/improved relative to baseline during progression-free time (during treatment, up to 12 cycles of monotherapy, both arms), with a trend for a decline at progression (44% BEV+RT/TMZ and 49% Plb+RT/TMZ stable/improved). NCF substudy: n=34 BEV+RT/TMZ; n=33 Plb+RT/TMZ. Demographics were generally balanced (except fewer females BEV+RT/TMZ [29%] versus Plb+RT/TMZ [42%]). Completion rates (both arms): 88-100% ≤52wks after baseline; 73-89% at the time of progression. Relative to baseline, during progression-free time, RCI-determined stable/improved NCF was seen in (BEV+RT/TMZ versus Plb+RT/TMZ): 82%/64% (HVLT-R-A); 85%/73% (HVLT-R-B); 74%/70% (HVLT-R-C); 79%/73% (TMT-A); 71%/67% (TMT-B); 85%/73% (COWA). The duration of stable/improved NCF during progression-free time was longer for BEV+RT/TMZ (mean duration 8.0-9.5 months across all tests) versus Plb+RT/TMZ (mean duration 5.0-5.4 months across all tests), reflective of longer PFS. CONCLUSION: Measures of NCF, including MMSE and a small HVLT-R/TMT/COWA substudy, were maintained/improved during progression-free time for most patients in both study arms. Study Supported by: F. Hoffmann-La Roche Ltd Disclosure: Dr. Wefel has received personal compensation for activities with Roche Diagnostics Corp., Genentech Inc., and Eli Lilly & Co. Inc. Dr. Wefel has received research support from Roche Diagnostics Corp., and Genentech Inc. Dr. Chinot has received personal compensation for activities with F. Hoffmann-La Roche, AstraZeneca Pharmaceuticals, and Merck Sharp & Dohme Ltd. Dr. Chinot has received research support from F. Hoffmann-La Roche and Schering-Plough Corporation. Dr. Wick has received personal compensation for activities with Roche Diagnostics Corp., Merck Sharp & Dohme Ltd. Dr. Wick has received personal compensation in an editorial capacity for CNS Oncology. Dr. Wick has received research support from Boehringer Ingelheim Pharmaceuticals Inc., Apogenix, and Merck Sharp & Dohme Ltd. Dr. Mason has received personal compensation for activities with Roche Diagnostics Corporation. Dr. Henrisksson has received personal compensation for activities with F. Hoffmann-La Roche. Dr. Saran has received personal compensation for activities with Roche Diagnostics Corp. Dr. Nishikawa has received personal compensation for activities with F. Hoffman–La Roche. Dr. Revil has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Garcia has received personal compensation for activities with F. Hoffmann-La Roche Ltd. as an employee. Dr. Cloughsey has received personal compensation for activities with F. Hoffman-La Roche, Genentech Inc., Merck & Co. Inc., Merck & Co. Inc., Serono Inc., Celgene, Tocagen, Apogenix, and Newgen.