Ctni-18. Dual Inhibition of Post-Radiogenic Revascularization in Newly-Diagnosed Glioblastoma: Final Results of the Multicentric Phase 1/2 Gloria Trial

BACKGROUND Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). Despite prolonging progression-free survival (PFS) in prior phase 3 trials, VEGF-targeted angiogenesis inhibition failed to translate into an overall survival (OS) benefit, highlighting the urgent need for alternative or combinatorial strategies to durably disrupt post-radiogenic tumor revascularization. We previously reported interim data from the multicentric phase 1/2 GLORIA trial (NCT04121455) investigating CXCL12-targeted anti-vascular therapy as a novel approach for newly-diagnosed GBM. METHODS Concurrently with trial conduct, we performed spatial expression analyses, providing a rationale for dual inhibition of VEGF and CXCL12, two non-redundant, spatially distinct acting factors in tumor revascularization. Subsequently, we expanded the ongoing trial, which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed IDH-wildtype GBM (CNS WHO grade 4) lacking MGMT promoter methylation. Six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. The primary endpoint was safety. Secondary endpoints included radiographic response according to modified RANO criteria (mRANO) as well as perfusion imaging and clinical outcome. RESULTS Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. One patient achieved complete remission, four partial response and one stable disease. Median PFS and OS after RT+BEV+NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT+NOX-A12 (p=0.009; p=0.021) with two patients exceeding 2-year OS. CONCLUSIONS Our findings establish proof-of-principle that dual inhibition of angio- and vasculogenesis via blockade of VEGF and CXCL12 is a safe and promising targeted strategy for patients with newly-diagnosed GBM following RT.