VBL Therapeutics announced the publication of clinical data from the Phase 2 and Phase 3 studies of VB-111 (ofranergene obadenovec) in recurrent glioblastoma (rGBM) in two manuscripts published in the peer-reviewed journal Neuro-Oncology, the official journal of the Society for Neuro-Oncology. In the Phase 2 study, patients with rGBM who were primed with VB-111 monotherapy that was continued after progression with the addition of bevacizumab (Avastin®) showed significant survival (414 vs 223 days; HR 0.48; p=0.043) and progression free survival (PFS) advantage (90 vs 60 days; HR 0.36; p=0.032) compared to a cohort of patients that had limited exposure to VB-111. Radiographic responders to VB-111 exhibited specific imaging characteristics related to its mechanism of action. Survival advantage was also seen in comparison to historic controls, with the percentage of patients living more than one year doubling from 24% to 57%. The GLOBE Phase 3 study, top-line data from which were announced in 2018, compared upfront concomitant administration of VB-111, without priming, and bevacizumab to bevacizumab monotherapy. In this modified regimen, the treatment did not improve overall survival (OS) and PFS outcomes in rGBM. The new manuscript by Cloughesy et al. attributes the contradictory outcomes between the Phase 2 and Phase 3 trials as being related to the lack of VB-111 monotherapy priming in the GLOBE study, providing clinical, mechanistic and radiographic support for this hypothesis. Notably, GLOBE data show improved outcomes associated with a post VB-111 fever reaction, similar to outcomes from previous VB-111 studies, providing further support that fever is a potential biomarker for better survival with VB-111, secondary to the drug’s immunologic mechanism of action.