445MO - Dual inhibition of post-radiogenic angio-vasculogenesis in glioblastoma: Results of the phase I/II GLORIA trial

Background

The hypoxia-induced factors CXCL12 and VEGFA promote glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating revascularization. We previously reported safety and efficacy signals for RT and the CXCL12 neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) in the multicenter phase I/II GLORIA trial (NCT04121455). Here, we report data from exploratory tissue analysis and clinical outcomes for dual inhibition of vasculo- (NOX-A12) and angiogenesis (bevacizumab, BEV) in GBM in the first expansion arm.

Methods

GBM tissue samples were analyzed by spatial omics to explore regulation and cellular sources of CXCL12 and VEGFA expression. Six patients with newly diagnosed, incompletely resected, MGMT-unmethylated GBM were enrolled, receiving RT (60 Gy), NOX-A12 (600 mg/week i.v.) and BEV (10 mg/kg q2w i.v.). The primary endpoint was safety. Secondary endpoints included radiographic response. Findings were compared to patients who had received RT + NOX-A12 only (n=10) and patients with comparable characteristics treated with standard-of-care (SOC, n=22).

Results

While VEGFA was strongly expressed in the hypoxic perinecrotic areas, high levels of CXCL12 were also detected in the infiltration and microvascular proliferation zones, suggestive of both shared and distinct regulatory mechanisms requiring dual therapeutic targeting of CXCL12 and VEGFA. RT + NOX-A12 + BEV was well-tolerated and safe. Of all G≥2 AEs (n=96), two G2 events (2.1%) were deemed related to NOX-A12 only. Under treatment, one patient achieved confirmed complete response, four partial response and one stable disease (83.3% overall response). Median best change from baseline of the highly perfused GBM fraction was -98.1 (-61.3 to -100) %. Median progression-free survival and overall survival (OS) were 9.1 months and 19.9 months, significantly outperforming both RT + NOX-A12 only and SOC (p=0.005). Two patients surpassed 2-year OS, with follow-up ongoing for one.

Conclusions

Post-radiogenic VEGF-driven angiogenesis and CXCL12-driven vasculogenesis are complementary and non-redundant, spatially distinctive mechanisms facilitating GBM recurrence. Combinatory inhibition by NOX-A12 + BEV is safe and yields promising clinical outcomes.

Clinical trial identification

NCT04121455; EudraCT Number: SNOXA12C401 2018-004064-62.

Editorial acknowledgement

Legal entity responsible for the study

TME Pharma AG.

Funding

TME Pharma AG.

Disclosure

F.A. Giordano: Financial Interests, Personal, Advisory Board: AstraZeneca, Carl Zeiss Meditec AG, Cureteq, Guerbet SA, TME Pharma AG, TME Pharma AG, Novocure; Financial Interests, Personal, Invited Speaker: MEDAC AG; Financial Interests, Personal, Stocks/Shares: TME Pharma AG; Financial Interests, Personal, Advisory Board, Book Editor: Elsevier; Financial Interests, Institutional, Coordinating PI, GLORIA Trial: TME Pharma AG; Financial Interests, Institutional, Coordinating PI, INTRAGO Trial: Carl Zeiss Meditec AG; Financial Interests, Institutional, Local PI: Guerbet SA, MSD Sharp & Dohme GmbH; Non-Financial Interests, Institutional, Product Samples: myoncare GmbH; Non-Financial Interests, Leadership Role: Gemeinsam gegen Glioblastom; Non-Financial Interests, Advisory Role: yeswecan!cer. J.P. Layer: Financial Interests, Personal, Stocks/Shares: TME Pharma AG, Siemens Healthineers AG, Bayer AG, BioNTech AG; Financial Interests, Personal, Sponsor/Funding, Travel expenses: TME Pharma AG, Carl Zeiss Meditec; Financial Interests, Personal, Financially compensated role, KOL: Carl Zeiss Meditec; Financial Interests, Personal, Advisory Role: Siemens Healthineers AG. O. Mirallas: Financial Interests, Personal, Invited Speaker: ROVI; Financial Interests, Institutional, Writing Engagement: Roche, Merck; Other,Travel Expenses: Kyowa kirin, Almirall; Other, Travel Expenses and Conference Fee: Sanofi; Other, Travel expenses: Recordati. M. Hölzel: Financial Interests, Institutional, Sponsor/Funding: TME Pharma AG; Financial Interests, Personal, Sponsor/Funding, Travel expenses: TME Pharma AG. All other authors have declared no conflicts of interest.