DNAR-08. Phase I Trial of Peposertib (DNA-PK inhibitor) Plus Radiation in Newly Diagnosed MGMT-Unmethylated Glioblastoma, Updated Clinical, Radiographic, and Biomarker Outcomes

BACKGROUND DNA-dependent protein kinase (DNA-PK) facilitates DNA repair and reduces the effectiveness of DNA-damaging treatments such as radiation therapy (RT), making it an attractive target in glioblastoma. Peposertib, a selective DNA-PK inhibitor, has demonstrated preclinical efficacy in sensitizing GBM to RT, resulting in tumor regression. METHODS 21 adult patients with newly diagnosed GBM received peposertib concurrently with 60Gy RT over 6 weeks, followed by at least 6 cycles adjuvant TMZ (NCT04555577). RT-induced changes (i.e. pseudoprogression and radiation-necrosis) were assessed through conventional MRI and confirmed with spectroscopy and perfusion or pathology. Fractional Tumor Burden (FTB) were generated from Dynamic Susceptibility Contrast-(DSC)-MRI using relative cerebral blood volume thresholds to differentiate viable tumor from treatment-effect. γ-H2AX immunohistochemistry was performed on all available samples. RESULTS The maximum-tolerated dose of peposertib with RT was 300mg. After a median follow-up of 16.9 months (13.9 – 23.2), mPFS was 10.7 months (95%CI: 8.9-18.2) and mOS was 19.5 months (95%CI: 14.3-30.4). Among 18 evaluable patients, 6 (33%) had distant and 12 (66%) had local recurrence. RT-induced changes occurred in 9 of 19 patients (47%) and were associated with longer PFS (log-rank p = 0.031). In 9 patients with available DSC-MRI, FTB map analysis showed a trend toward increased treatment-effect volume at 4 weeks post-RT compared to immediate post-RT (median +9.4%, p = 0.195). γ-H2AX staining in 5 recurrent samples compared to 20 archival samples showed a trend toward higher post-treatment positivity (+14.4%, p = 0.112). Baseline γ-H2AX expression was not associated with survival outcomes. CONCLUSION Updated outcomes remain encouraging and support further development of peposertib. High rate of distant recurrence and positive association between RT-induced changes and PFS suggest that peposertib is active as a radiosensitizer. Further genomic, transcriptomic, and spatial proteomic analyses, are underway and will be presented at the conference. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).