Radiolabeled Somatostatin Receptor Antagonist Versus Agonist for Peptide Receptor Radionuclide Therapy in Patients with Therapy-Resistant Meningioma: PROMENADE Phase 0 Study

Abstract

Our primary aim was to compare the therapeutic index (tumor-to- bone marrow and tumor-to-kidney absorbed-dose ratios) of the new radiolabeled somatostatin receptor antagonist [177Lu]Lu-DOTA-JR11 with the established radiolabeled somatostatin receptor agonist [177Lu]Lu-DOTATOC in the same patients with progressive, standard therapy-refractory meningioma. Methods: In this prospective, singlecenter, open-label phase 0 study (NCT04997317), 6 consecutive patients were included: 3 men and 3 women (mean age, 63.5 y). Patients received 6.9-7.3 GBq (standard injected radioactivity) of [177Lu]Lu-DOTATOC followed by 3.3-4.9 GBq (2 GBq/m2 3 body surface area) of [177Lu]Lu-DOTA-JR11 at an interval of 1061 wk. In total, 1 [177Lu]Lu-DOTATOC and 2-3 [177Lu]Lu-DOTA-JR11 treatment cycles were performed. Quantitative SPECT/CT was done at approximately 24, 48, and 168 h after injection of both radiopharmaceuticals to calculate meningioma and organ absorbed doses as well as tumor-to-organ absorbed-dose ratios (3-dimensional segmentation approach for meningioma, kidneys, liver, bone marrow, and spleen). Results: The median of the meningioma absorbed dose of 1 treatment cycle was 3.4Gy (range, 0.8-10.2Gy) for [177Lu]Lu-DOTATOC and 11.5Gy (range, 4.7-22.7Gy) for [177Lu]Lu-DOTA-JR11. The median bone marrow and kidney absorbed doses after 1 treatment cycle were 0.11Gy (range, 0.05-0.17Gy) and 2.7Gy (range, 1.3- 5.3Gy) for [177Lu]Lu-DOTATOC and 0.29Gy (range, 0.16-0.39Gy) and 3.3Gy (range, 1.6-5.9Gy) for [177Lu]Lu-DOTA-JR11, resulting in a 1.4 (range, 0.9-1.9) times higher median tumor-to-bone marrow absorbed-dose ratio and a 2.9 (range, 2.0-4.8) times higher median tumor-to-kidney absorbed-dose ratio with [177Lu]Lu-DOTA-JR11. According to the Common Terminology Criteria for Adverse Events version 5.0, 2 patients developed reversible grade 2 lymphopenia after 1 cycle of [177Lu]Lu-DOTATOC. Afterward, 2 patients developed reversible grade 3 lymphopenia and 1 patient developed reversible grade 3 lymphopenia and neutropenia after 2-3 cycles of [177Lu]Lu- DOTA-JR11. No grade 4 or 5 adverse events were observed at 15mo or more after the start of therapy. The disease control rate was 83% (95% CI, 53%-100%) at 12mo or more after inclusion. Conclusion: Treatment with 1 cycle of [177Lu]Lu-DOTA-JR11 showed 2.2-5.7 times higher meningioma absorbed doses and a favorable therapeutic index compared with [177Lu]Lu-DOTATOC after injection of 1.4-2.1 times lower activities. The first efficacy results demonstrated a high disease control rate with an acceptable safety profile in the standard therapy for refractory meningioma patients. Therefore, larger studies with [177Lu]Lu-DOTA-JR11 are warranted in meningioma patients.