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Oral Presentation

Tumor

Journal of Neuro-Oncology Award: Summary findings of a surgical window-of-opportunity clinical trial evaluating the PCSK9 inhibitor Evolocumab in patients with glioma

Saturday, May 4, 2024
2:24 PM – 2:28 PM CT
Location:  S401ab
Disclosure(s):
Kirit Singh, MD: No financial relationships to disclose
Introduction: Primary tumors of the CNS can circumvent immune detection by reducing major histocompatibility class (MHC)-I expression. Recently, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been found to prevent MHC-I internalization and degradation. FDA approved monoclonal antibodies that inhibit PCSK9 (Evolocumab) are currently indicated for hyperlipidemia. We present final summary findings of a prospective window of opportunity study (PESKe, NCT04937413) that evaluated if Evolocumab could 1) be detected in tumors of patients with newly diagnosed or recurrent glioma and 2) alter MHC-I expression.

Methods: 30 patients were consented (16M, 14F) with 24 assigned to controls and 6 assigned to intervention. Patients assigned to intervention received 420mg Evolocumab SC 4 days prior to planned resection of tumor. Tumors were analyzed via mass spectroscopy to quantitate drug, as well as IHC and Immunofluorescence to assess for MHC-I expression.

Results: No serious adverse events were recorded in patients receiving Evolocumab. To detect Evolocumab (EVO) in tumor via LC-MS/MS, we identified peptide sequences not in the human proteome. We evaluated these proteotypic peptides, identifying a specific marker for Evolocumab. Evolocumab was detected in all analyzed intervention samples, with higher signal being detected in patients with contrast-enhancing lesions. LC-MS/MS quantitation of HLA-A, B & C shows median increases in intervention vs control. Immunofluorescence found that tumors with low Evolocumab uptake exhibit a small increase in MHC-I compared to control. Tumors with high uptake of Evolocumab had markedly increased MHC-I.

Conclusion : At the conclusion of this study, no significant Adverse Events were seen, even while treating at the maximum dose. Evolocumab was detected in all treated samples although intra-tumoral levels varied, mirroring the degree of contrast enhancement. In tumors with high Evolocumab, high MHC-I expression was observed. Future studies will evaluate combinatorial strategies with Evolocumab (+/-Ipilimumab +/-Nivolumab) as well as potentially stratifying treatment only to contrast-enhancing tumors.