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

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

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Eligibility criteria are very similar for most studies: (i) age > 18 years, (ii) PS (KPS > 60–70), (iii) IDH-wildtype status, (iv) prior chemotherapy delivered at least 4 weeks before initiation of experimental therapy, (v) last radiotherapy session delivered at least 7 weeks before initiation of experimental therapy and (vi) known MGMT promoter methylation status [ 14 , 73 ]. The endpoints are median PFS, median OS, PFS6, and OS12 (OS at 12 months) [ 14 , 73 , 74 , 75 ].…”

“…This approach failed to improve survival when compared to standard of care [ 5 , 82 ]. Another viral therapy, ofranergene obadenovec (VB-111), a non-replicating adenovirus carrying a Fas-chimera transgene tested with Bevacizumab did not ensure survival advantage when compared to Bevacizumab alone [ 75 , 83 ]. Overall, a limited number of recurrent GBM respond to immunotherapy.…”

Current Advances in Immunotherapy for Glioblastoma

“…2) mOS: 7.9 mos. (HR, 1.20; 95% CI: 0.91–1.59; P = 0.19) [ 85 ] DNX-2440 NCT03714334 DNX-2440 (OX40L adenoviral vector) I ( n = 24) Recurrent GBM Ongoing M032-HSV-1 NCT02062827 M032-HSV-1 (2nd-gen. HSV) with IL-12 I ( n = 36) Recurrent GBM Ongoing IDH mutant glioma: Vaccine RESIST NCT02193347 IDH peptide vaccine (PEPIDH1M) + TMZ I ( n = 24) Recurrent Grade II glioma, IDH mutant Ongoing NOA-16 NCT02454634 IDH1R132H peptide vaccine, montanide, imiquimod I ( n = 39) Newly diagnosed AA and GBM; IDH1R132H mutant 80% specific T cell response; 87% with specific humoral response [ 86 ] IDH mutant glioma: Combination therapy NCT03532295 INCMGA00012 (anti-PD1) + epacadostat + bevacizumab + RT II ( n = 55) Recurrent GBM IDH wildtype or mutant Recruiting NCT03422094 NeoVax, ipilimumab, nivolumab I ( n = 3) Newly diagnosed MGMT Unmethylated, IDH1/IDH2 mutant GBM Ongoing Pediatric: Adoptive cell therapy NCT04196413 GD2-CAR T cells I ( n = 54) DMG with H3.3 K27M mutation Recruiting NCT04185038 B7H3-CAR T cells I ( n = 70) DMG, or recurrent CNS tumor Recruiting NCT03389230 HER2(EQ)BBζ/CD19t+ T cells I ( n = 42) Recurrent, HER2 + HGG Recruiting NCT03500991 I ( n = 48) Refractory or recurrent, HER2+ pediatric CNS tumor Recruiting NCT03638167 EGFR806-CAR T cells I ( n = 36) EGFR + refractory or recurrent CNS tumor Recruiting …”

MiR-9 Promotes Angiogenesis via Targeting on Sphingosine-1- Phosphate Receptor 1

“…Anti-angiogenic therapies (AATs) have been developed to combat tumor metastasis (Hosein et al, 2020). Nowadays, AATs strategies include blood vessel pruning, disruption or normalization of the tumor vasculature, and tumor immunosensitization but did not yield satisfactory efficacy (Cully, 2017;Cloughesy et al, 2020). Bevacizumab antagonizes vascular endothelial growth factor (VEGF) to induce vascular normalization and therefore reduce edema.…”

“…Bevacizumab antagonizes vascular endothelial growth factor (VEGF) to induce vascular normalization and therefore reduce edema. Vascular disruptive agents such as VB-111 disrupts the angiogenic vasculature via promoting tumor starvation and enhancing the vascular permeability in the tumor environment to increase edema and recruit the immune cells ( Cloughesy et al, 2020 ). AATs and immune checkpoint inhibitors were combined to acquire promising outcomes of cancer patients ( Yi et al, 2019 ).…”