Bortezomib (26S proteasome/NF-κB inhibition) + sequential temozolomide extends OS to 18.8 months in recurrent uMGMT GBM

Sequential bortezomib (BTZ), an IV 26S proteasome inhibitor that can suppress NF-κB signaling and deplete MGMT protein, was given 48 hours before temozolomide (TMZ) in the BORTEM-17 Phase IB/II recurrent glioblastoma study (NCT03643549) in Norway. In recurrent uMGMT-promoter GBM progressing ≥12 weeks post-radiotherapy (n=62; median KPS 90), BTZ 1.3mg/m² IV days 1/4/7 plus TMZ 200mg/m² PO starting day 3 (5 days/week) produced a 24% RANO response rate (15/62) and an adjusted median OS of 18.8 months vs 12.9 months in matched hospital controls (HR 0.68, p=0.008); by comparison, commonly used recurrent-GBM benchmarks such as regorafenib vs lomustine in REGOMA delivered mOS 7.4 vs 5.6 months, and bevacizumab-containing approaches improve PFS more than OS in randomized data. Safety was described as mostly mild/moderate; notable events included grade 4 thrombocytopenia (reported as 4/7 events) resolving during breaks and 33 grade 3 AEs (including seizures/back pain), with stable EQ-5D-5L QoL; biomarker signals suggested responders retained RTK/NF-κB/PI3K pathway components (e.g., EGFR/FGFR3 gains), consistent with NF-κB “dependence” as a potential sensitization axis.