CTNI-44. NCT03643549 PHASE IB/II TRIAL: EFFICACY, SAFETY, AND BIOLOGICAL MECHANISMS OF OBJECTIVE RESPONSES IN RECURRENT GBM PATIENTS WITH UNMETHYLATED MGMT PROMOTER TREATED WITH SEQUENTIAL BORTEZOMIB AND TEMOZOLOMIDE

Abstract BACKGROUND Glioblastoma (GBM) is amongst the deadliest malignancies in adults, but especially for patients with unmethylated MGMT promoter (uMGMT) who gain limited benefit from the standard treatment. We previously demonstrated that proteosome inhibitor bortezomib (BTZ), inhibited NFkB activation,depleted MGMT protein and sensitized uMGMT GBM cells to Temozolomide (TMZ). Thus, a phase I/II trial testing sequential combination BTZ+TMZ was launched to investigate safety and clinical benefit. METHODS Recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, KPS≥70 and radiologically measurable lesions were enrolled. The trial was powered for n=63 patients compared with n=102 historical controls. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, starting on day 3 with oral 200mg/m² TMZ for 5 days/week. Whole exome sequencing (WES) of tumor DNA was conducted to identify genetic changes and LC-MS/MS used to asses proteomic changes in plasma collected during treatment. RESULTS As of January 2024, 54 patients (median 55y (25-70); 38 males, 16 females) were treated. The median KPS 90 (range 70-100) and NANO score was 1 (range 0-7). QoL was preserved, with mild /moderate adverse events. Adjusted analyses showed overall survival (OS) of 16.2 months compared to 8.4 months for uMGMT control patients, HR0.48, 95%CI[1.057-2.74],P=0.028. Objective radiological responses stable disease or better were observed in 22% (12/54) patients. Survival from recruitment was 10.5 months for responders vs. 4.8 months for rest of cohort, P=0.054 HR2.55, 95%CI[0.984-5.94]. Preliminary data indicate 78% (7/9) of responders harboured amplified EGFR vs. 38% in rest-of-the patients. The responders differentially expressed proteins critical for cellular processes, including ADAMTSL4, NCAM1, AZGP1, MMP2, CD163, and IL6ST. CONCLUSION Sequential BTZ+TMZ therapy is safe, effective and showed clinical benefit. EGFR amplification may be a predictive biomarker for response through NFκB activation, that is targeted by BTZ thereby depleting MGMT protein and enhancing treatment efficacy. Sequential BTZ+TMZ treamtment may represent additional treatment option at recurrence.