Prospective phase II trial of [68Ga]Ga-NOTA-AE105 uPAR-PET/MRI in patients with primary gliomas: Prognostic value and Implications for uPAR-targeted Radionuclide Therapy

Abstract

Background: Treatment of patients with low-grade and high-grade gliomas is highly variable due to the large difference in survival expectancy. New non-invasive tools are needed for risk stratification prior to treatment. The urokinase plasminogen activator receptor (uPAR) is expressed in several cancers, associated with poor prognosis and may be non-invasively imaged using uPAR-PET. We aimed to investigate the uptake of the uPAR-PET tracer [⁶⁸Ga]Ga-NOTA-AE105 in primary gliomas and establish its prognostic value regarding overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the proportion of uPAR-PET positive tumors to estimate the potential number of candidates for future uPAR-PRRT.

Methods: In a prospective phase II clinical trial, 24 patients suspected of primary glioma underwent a dynamic 60-min PET/MRI following the administration of approximately 200 MBq (range: 83-222 MBq) [⁶⁸Ga]Ga-NOTA-AE105. Lesions were considered uPAR positive if the tumor-to-background ratio, calculated as the ratio of TumorSUVmax-to-Normal-BrainSUVmean tumor-SUVmax-to-background-SUVmean, was ≥ 2.0. The patients were followed over time to assess OS and PFS and stratified into high and low uPAR expression groups based on TumorSUVmax.

Results: Of the 24 patients, 16 (67%) were diagnosed with WHO grade 4 gliomas, 6 (25%) with grade 3, and 2 (8%) with grade 2. Two-thirds of all patients (67%) presented with uPAR positive lesions and 94% grade 4 gliomas. At median follow up of 18.8 (2.1-45.6) months, 19 patients had disease progression and 14 had died. uPAR expression dichotomized into high and low, revealed significant worse prognosis for the high uPAR group for OS and PFS with HR of 14.3 (95% CI, 1.8-112.3; P = 0.011), and HR of 26.5 (95% CI, 3.3-214.0; P = 0.0021), respectively. uPAR expression as a continuous variable was associated with worse prognosis for OS and PFS with HR of 2.7 (95% CI, 1.5-4.8; P = 0.0012), and HR of 2.5 (95% CI, 1.5-4.2; P = 0.00073), respectively.

Conclusions: The majority of glioma patients and almost all with grade 4 gliomas displayed uPAR positive lesions underlining the feasibility of ⁶⁸Ga-NOTA-AE105 PET/MRI in gliomas. High uPAR expression is significantly correlated with worse survival outcomes for patients. Additionally, the high proportion of uPAR positive gliomas underscores the potential of uPAR-targeted radionuclide therapy in these patients.

Trail registration: EudraCT No: 2016-002417-21; the Scientific Ethics Committee: H-16,035,303; the Danish Data Protection Agency: 2012-58-0004; clinical trials registry: NCT02945826, 26Oct2016, URL: https://classic.

Clinicaltrials: gov/ct2/show/NCT02945826 .

Keywords: Glioma; Molecular imaging; PET/MRI; Prognosis; Targeted radionuclide therapy; Urokinase plasminogen activator receptor (uPAR).

Fig. 1

Consolidated standards of reporting trials (CONSORT) flow diagram of inclusion process

Fig. 2

Spaghetti plot illustrating individual trajectories of TumorSUVmax values measured at timepoints 20–40 min and 40–60 min after tracer injection. Each line represents a unique participant (N = 22). The plot reveals consistent TumorSUVmax values over time across the study population, emphasizing stability in the measurements over time

Fig. 3

Bland-Altman plot displaying the agreement between TumorSUVmax values measured at timepoints 20–40 min and 40–60 min after tracer injection. The red line represents the mean difference, and the green lines indicate the 95% limits of agreement calculated as mean difference +/- 1.96 SD. Percentage agreement within 1.96 standard deviations is 95.45%, demonstrating high concordance between the two timepoints

Fig. 4

Examples of uPAR PET/MRI performed on patient with glioblastoma, IDH-wildtype, WHO Grade 4 (MGMT non-methylated) in the temporoparietal lobe with tumor SUVmax 3.3: #A T1W MPRAGE MRI with gadolinium contrast, #B T2W FLAIR MRI image, #C uPAR-PET image, #D Merged T2W FLAIR MRI, and uPAR-PET image. Color scale from 0 to tumor SUVmax value of 3.3

Fig. 5

Examples of uPAR PET/MRI performed on patient with glioblastoma, IDH-wildtype, WHO Grade 4 (MGMT non-methylated) involving the genu corpus callosum with tumor SUVmax 2.2: #A T1W MPRAGE MRI with gadolinium contrast, #B T2W FLAIR MRI image, #C UPAR-PET image, #D Merged T2W FLAIR MRI, and uPAR-PET image. Color scale from 0 to tumor SUVmax value of 2.2

Fig. 6

For all primary gliomas Kaplan-Meier Survival plots of OS and PFS dichotomized at SUVmax 0.635

Fig. 7

For all primary HGG Kaplan-Meier Survival plots of OS and PFS both dichotomized at SUVmax 1.1