Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours

Abstract

Purpose: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [¹⁷⁷Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs).

Methods: This study was part of a phase I/II trial of [¹⁷⁷Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients.

Results: In all evaluated organs, maximum [¹⁷⁷Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [¹⁷⁷Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [¹⁷⁷Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles.

Conclusion: [¹⁷⁷Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy.

Trial registration: NCT02592707. Registered October 30, 2015.

Keywords: Dosimetry; Neuroendocrine tumours; Pharmacokinetics; Somatostatin receptor antagonist; Systemic radionuclide therapy; [177Lu]Lu-satoreotide tetraxetan.

Fig. 1

Administered activity and peptide amounts of [¹⁷⁷Lu]Lu-satoreotide tetraxetan in cycles 1 to 3 of part A and part B of the study [24]. Note that four patients in cohort 3 and two patients in cohort 6 received additional treatment cycles. The study had a SRC (part A) and a DRB (part B). During part B, each escalation cohort (whether of administered activity or peptide amount) was evaluated by the DRB. The DRB recommended the cohort 1 administered activity be reduced from 6.0 GBq to 4.5 GBq due to safety concerns, and therefore the planned cohorts 2, 4, 5, 7 and 8, which would have included administered activities of more than 4.5 GBq, were not performed. Of the 40 included patients, 36 underwent dosimetry evaluation. Among them, 33 patients were treated with a [¹⁷⁷Lu]Lu-satoreotide tetraxetan cycle of 4.5 GBq (part A: N = 11 [cycles 1–3]; part B: N = 22 [cycles 1–3 in cohort 1, cycles 1–3 in cohort 3, cycles 1–3 in cohort 6]) and three were treated with a [¹⁷⁷Lu]Lu-satoreotide tetraxetan cycle of 6 GBq (cycle 1 of cohort 1 in part B). DRB: Data Review Board; SRC: Safety Review Committee

Fig. 2

Uptake of [¹⁷⁷Lu]Lu-satoreotide tetraxetan after administration of the first treatment cycle in parts A and B. Per protocol dosimetry analysis set (N = 36). Data are presented as median (range), in percentage of administered activity or % of administered activity/L for blood uptake. Lines are not directly related to the fit of the data and should be used as a guide only. The grey dashed line represents 100% uptake

Fig. 3

Cumulative absorbed doses of [¹⁷⁷Lu]Lu-satoreotide tetraxetan in evaluated organs after administration of three [¹⁷⁷Lu]Lu-satoreotide tetraxetan cycles in parts A and B. Per protocol dosimetry analysis set (N = 36). Data are presented as mean, median (minimum, Q1, Q2, Q3, maximum) for parts A and B in box plot; scatter plots represent individual patient data for parts A and B. Q1: quartile 1; Q2: quartile 2; Q3: quartile 3