A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 22; no. 5; pp. 705 - 717
• Main Authors: Cloughesy, Timothy F, Brenner, Andrew, de Groot, John F, Butowski, Nicholas A, Zach, Leor, Campian, Jian L, Ellingson, Benjamin M, Freedman, Laurence S, Cohen, Yael C, Lowenton-Spier, Noa, Rachmilewitz Minei, Tamar, Fain Shmueli, Shifra, Wen, Patrick Y
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 15.05.2020
• Subjects: Angiogenesis Inhibitors - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab - therapeutic use; Brain Neoplasms - drug therapy; Clinical Investigations; Glioblastoma - drug therapy; Humans; Progression-Free Survival; Treatment Outcome; VB-111; gene therapy; viral immuno-oncology; glioblastoma; anti-angiogenesis
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noz232

Abstract Background Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. Methods This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). Results Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. Conclusions In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. Clinical trials registration NCT02511405