Potential of PSMA-targeting radioligand therapy for malignant primary and secondary brain tumours using super-selective intra-arterial administration: a single centre, open label, non-randomised prospective imaging study

Background The aim of this study was to provide quantitative evidence for the potential of PSMA-targeting radioligand therapy (RLT) as treatment approach for malignant brain tumours, and to explore whether tumour uptake could be enhanced by super-selective intra-arterial (ssIA)-administration. Methods Ten patients (n = 5 high-grade glioma, n = 5 brain metastasis) received 1.5 MBq/kg [68Ga]Ga-PSMA-11 intravenously and, within 7 days, intra-arterially (i.e., selectively in tumour-feeding arteries), followed twice by PET-MRI at 90, 165 and 240 min post-injection. Patient safety was monitored for each procedure. Standardised uptake values (SUVs) were obtained for tumour, healthy-brain, salivary glands and liver. Tumour-to-salivary-gland (T/SG) and tumour-to-liver (T/L) uptake-ratios were calculated. Findings No adverse events requiring study termination occurred. All patients showed uptake of [68Ga]Ga-PSMA-11 at the tumour site. Uptake was a median 15-fold higher following ssIA-administration (SUVmax median: 142.8, IQR: 102.8–245.9) compared to IV-administration (10.5, IQR:7.5–13.0). According to the bootstrap analysis, mean SUVmax after ssIA (168.8, 95% CI: 110.6–227.0) was well beyond the 95% confidence-interval of IV administration (10.5, 95% CI: 8.4–12.7). Uptake in healthy-brain was negligible, independent of administration route (SUVmean <0.1–0.1). Off-target uptake was comparable, resulting in more favourable T/SG- and T/L-ratios of 8.4 (IQR: 4.4–11.5) and 26.5 (IQR: 14.0–46.4) following ssIA, versus 0.5 (IQR: 0.4–0.7) and 1.8 (IQR: 1.0–2.7) for IV-administration. Interpretation ssIA-administration is safe and leads to a median fifteen-fold higher radioligand uptake at the tumour site, therewith qualifying more patients for treatment and enhancing the potential of therapy. These results open new avenues for the development of effective RLT-based treatment strategies for patients with brain tumours. Funding Semmy Foundation.