Abstract CT274: Inhibiting 26S proteosome with sequential bortezomib and temozolomide garners 5 months prolonged survival in recurrent MGMT-negative GBM through amplified tyrosine kinase receptor signaling to avail NF-kB mechanistic target in NCT0364

Abstract Glioblastoma (GBM) is a hard to treat primary brain tumor in adults, especially for patients with unmethylated O6-methylguanine DNA methyltransferase (uMGMT) promoter. We previously demonstrated the proteasome inhibitor bortezomib (BTZ) administered 48hrs before temozolomide (TMZ) depletes MGMT protein, disrupts autophagic flux, inhibits NF-κB signaling, and chemosensitizes uMGMT GBM cells. In our phase IB, TMZ dose escalation in combination with BTZ was safe, and interim analysis indicated potential clinical benefit. Thus, full recruitment in phase II trial was launched to investigate clinical benefit and biomarkers for response. 62 recurrent GBM patients with uMGMT promoter, progressing ≥ 12 weeks after radiotherapy, KPS ≥ 70 and with measurable recurrent lesions were enrolled. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, TMZ starting on day 3 with oral at 200mg/m² for 5 days/week. Adverse events (AE) used CTCAE grading. Clinical evaluation included NANO, RANO, and EQ-5D-5L quality of life assessment. Kaplan-Meier and Cox regression were used to estimate survival probabilities and differences between matched control (n=118) patients treated at the same participating hospitals. Whole exome and RNA seq of tumor DNA were conducted to identify response associated molecular changes. Until January 2026,62 patients of median age of 55 (25-70 years), 45 males and 17 females, median KPS 90 (70-100) and NANO 1 (0-7) were treated at four university hospitals in Norway. AEs after addition of BTZ were limited to mild or moderate, where 4/7 were grade 4 thrombocytopenia that resolved during treatment breaks. 33 grade 3 AEs included seizures and backpain. Overall QoL was good and stable throughout the treatment (median 65, range 60-75). RANO objective radiological responses were observed in 24% (15/62) patients. Adjusted analyses showed OS benefit of 18.8 months (mos) for BORTEM-17 patients compared to 12.9 mos for controls with uMGMT (n=108) landmarked at 3 mos, HR0.68, 95%CI[0.49-0.94], P=0.008. Adjusting for IDH status, BORTEM-17 patients (n=55, IDH wt) OS was 17.9 vs. 12.9 mos for controls (n=108) HR0.71, 95%CI[0.51-1.06], P=0.009. Overall, median OS for responders was 23.7 vs. 18.7 mos for rest of patients, HR0.75, 95%CI [0.39-1.4], P=0.005. Responders survived 9.5 mos after recruitment compared to 5.0 mos for rest of patients, HR0.52, 95%CI [0.27-0.99], P<0.035, with median time to progression 5.1 mos vs. 2.3, HR0.45, 95%CI [0.23-0.85], P<0.0001. Responders retained more receptor tyrosine kinase /NF-κB/PI3K pathway components, exemplified by copy-number gains in EGFR, FGFR3, and MAPK11, suggesting dependence on intact RTK signaling, availing NF-κB, that is the molecular target for BTZ. In contrast, rest cohort harbored copy-number loss of NFKB2, IKKα, PTEN and CDKN2, indicating NF-κB abrogation. RNA seq transcriptional profiling is ongoing. The sequential BTZ+TMZ therapy is safe, garners clinical benefit and may represent effective additional treatment for treatment refractory recurrent patients with exceptionally poor prognosis. The study is currently recruiting. ClinicalTrials.gov id: NCT03643549 Citation Format: Dorota Goplen, Mohummad Aminur Rahman, Surendra Kumar, Marianne H. Hannisdal, Victoria Arnesen, Andreas Waha, Leif Oltedal, Judit Haasz, Jorunn Brekke, Tora S. Solheim, Petter Brandal, Stein A. Lie, Martha Chekenya. Inhibiting 26S proteosome with sequential bortezomib and temozolomide garners 5 months prolonged survival in recurrent MGMT-negative GBM through amplified tyrosine kinase receptor signaling to avail NF-kB mechanistic target in NCT03643549 Phase IB/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT274.