Narsinh, Kazim

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, FDA-approved for hepatocellular carcinoma, offers the potential for targeted radiotherapy in recurrent GBM (rGBM). The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for rGBM under an FDA Investigational Device Exemption. Materials and METHODS This prospective, single-arm, multi-center study included patients with rGBM in non-dominant, non-eloquent regions. The primary endpoint was 30-day incidence of treatment-related limiting toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target), and efficacy. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion, were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET, and neurological assessments. RESULTS The procedure was well-tolerated by all twelve subjects and discharge occurred the following day with no decline in neurologic status. No limiting toxicities or device-related AEs were reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). Technical success was 100%, with post-treatment Y90-PET derived median absorbed dose of 41.5 Gy to the treatment region (median volume 80.3 cc). The median tumor absorbed dose was considerably higher at 124.2 Gy (median tumor volume 5.8 cc), indicating preferential tumor perfusion. At 2 months, 67% had stable disease, and 33% showed reduced T1-contrast enhancing volume within the treated area. Median progression-free survival was 3.1 (95% CI 0.92-NE) and overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (11.9 vs 5.7 months, p=0.0073). CONCLUSION Results from this initial cohort suggest IA Y90-microsphere therapy is technically feasible and well-tolerated in rGBM. Further investigation is warranted.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, CE-marked for hepatic neoplasia, offers the potential for targeted high-dose beta radiation in GBM by leveraging tumor hypervascularity. The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for recurrent GBM. MATERIAL AND METHODS FRONTIER is a prospective, single-arm, multi-center study with Investigational Device Exemption approval from the US FDA. This initial cohort included patients with recurrent GBM in non-dominant, non-eloquent regions after 1-2 lines of prior therapy. The primary endpoint was the 30-day incidence of treatment-related toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included overall treatment-related adverse events (AE), neurological function changes, technical success, and efficacy measures. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET for absorbed dose distribution, and serial neurological assessments. Changes in post-contrast T1-enhancing tissue volume (T1C-vol) were tracked longitudinally. RESULTS Twelve subjects (67% male; average age 57 years) were treated. The procedure was well-tolerated with no limiting toxicities reported or device-related AEs reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). At discharge one day after treatment, there was no decline in neurologic status per NIHSS. Technical success was 100%, with post-treatment Y90-PET showing a median absorbed dose of 41.5 Gy (range 39.2-45.4) to the treatment region (median volume 80.3 cc [40.9-118.5]). The median tumor absorbed dose was significantly higher at 124.2 Gy (range 58.5-508.5) within a median tumor volume of 5.8 cc (range 0.5-55.4), indicating preferential tumor perfusion. At 1 month, the best response was partial response in 17% (2/12), stable disease (SD) in 67% (8/12), and progressive disease in 17% (2/12). At 2 months, 73% (8/11 evaluable) had SD, and 33% (4/12) showed reduced T1C-vol within the treated area. Median progression-free survival was 3.0 (95% CI 1.1-3.7) and median overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (>124 Gy) compared to those below (13.1 vs 5.8 months, p=0.0054). CONCLUSION Results from this initial cohort of the FRONTIER trial suggest IA Y90 glass microsphere therapy is technically feasible and well-tolerated in patients with recurrent GBM. The observed dose-response relationship warrants further investigation of this modality as a potential treatment option.

Abstract BACKGROUND Yttrium-90 (Y90) microsphere treatment is an FDA-approved endovascular radiotherapy for Hepatocellular Carcinoma; however, extra-hepatic experience is limited. The FRONTIER trial (NCT05303467) is a first-in-human study conducted under an IDE from the FDA evaluating the safety and feasibility of intra-arterial Y90 endovascular radiotherapy in patients with recurrent glioblastoma (rGBM). METHODS The primary endpoint is the incidence of treatment-related limiting toxicities through 30 days, in 12 patients with rGBM. Eight subjects (50% male) with non-dominant hemisphere rGBM have been enrolled to date, with 6 patients reported herein. The treatment region, encompassing the recurrent lesion, excluding eloquent regions, and defined using cerebral angiography-MRI fusion, was selectively targeted with 40±4Gy. Immediate post-treatment imaging included MRI to evaluate acute treatment-related effects and Y90-PET to evaluate the absorbed dose distribution. Neurological assessments were performed pre- and post-treatment. Analysis of post-contrast T1w enhancing tissue volume (T1wvol) inside and outside the treated region was performed longitudinally. RESULTS All patients tolerated the procedure well and were discharged the following day. No decrease in neurological function and no limiting toxicities were reported through 30 days. Post-treatment MRI revealed no device-related acute ischemia or hemorrhage. Mean absorbed dose to the treatment region was 42.1±2.4Gy, within 3% of the targeted value, suggesting technical feasibility. Mean tumor absorbed dose within the treatment region was 65.1±22.6Gy most likely due to increased tumor perfusion in the treatment region. A reduction in T1wvol at 2m was observed in 4/6 patients, with the remaining 2 patients showing increased T1wvol. Disease progression by T1wvol occurred more rapidly outside the treatment region than within. All patients received subsequent therapy, with 2 patients receiving surgery 82 and 120 days post Y90 treatment. CONCLUSION Interim results in this first-in-human feasibility study demonstrated technical feasibility and no limiting toxicities through 30 days. Enrollment is ongoing. These data warrant additional investigation.