ACTR-05. THE RANDOMIZED PHASE II ARTE TRIAL: BEVACIZUMAB PLUS HYPOFRACTIONATED RADIOTHERAPY VERSUS RADIOTHERAPY ALONE IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT→TMZ) prolonged progression-free survival (PFS), but not overall survival (OS) in patients with newly diagnosed glioblastoma in two double-blind phase III trials. Elderly and frail patients are underrepresented in most clinical trials, but early reports of bevacizumab in glioblastoma suggested preferential benefit in this population. ARTE was a 2:1 randomized, multi-center, open-label trial of hypofractionated RT (40 Gy in 15 fractions) in combination with bevacizumab (10 mg/kg x 14 days) (arm A, N=50) versus RT alone (arm B, N=25) in patients with newly diagnosed glioblastoma aged >65 years. The primary endpoint was median OS. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Response was assessed by RANO criteria. Exploratory studies included 18 F-fluoro-ethyltyrosine positron emission tomography (FET-PET, N=34), as well as whole methylome (N=57) and nanostring gene expression (N=54) analyses. Median PFS was longer in arm A versus arm B (7.6 vs. 4.8 months, p=0.003), but OS was similar (12.1 vs 12.2 months, p=0.8). Clinical deterioration was delayed and more patients came off steroids in arm A versus arm B. Longer PFS in arm A versus arm B was confined to the receptor tyrosine kinase (RTK) I methylation subtype and to the proneural gene expression subtype, but was not observed for patients with RTK II, classical or mesenchymal subtype glioblastoma. Applying a Cox model to OS that controlled for established prognostic factors, we detected an association with age and KPS. Exploration of imaging predictors of OS in this model identified the presence of non-enhancing tumor detected by FET-PET (HR 0.31, p=0.02) as an important prognostic factor. Efficacy outcomes and exploratory analyses of ARTE do not support the notion that bevacizumab generally prolongs survival in elderly glioblastoma patients. However, novel molecular and imaging biomarkers may identify patients with preferential benefit from bevacizumab.