First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer
Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [177Lu]Lu-PSMA-617 therapy.
Thirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [68Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68 years) were treated with [177Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9 GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72 h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline.
Therapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1 h. Mean absorbed organ doses were 1.08 ± 0.44 Gy/GBq in the pancreas, 0.35 ± 0.14 Gy/GBq in the kidneys, 0.05 ± 0.02 Gy/GBq in the liver, 0.07 ± 0.02 Gy/GBq in the gallbladder wall, 0.10 ± 0.06 Gy/GBq in the spleen, and 0.02 ± 0.01 Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00 Gy/GBq.
Application of GRPr antagonist [177Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.
Keywords177Lu-RM2 Dosimetry Prostate cancer Dosimetry Radionuclide therapy Theranostics Gastrin-releasing peptide receptor
The authors are grateful to the radiopharmacy group for the production of [177Lu]Lu-RM-2 and the excellent technical support by the technicians.
All authors made substantial contributions to the conception of the study, analysis of the data, and/or interpretation of the results. J.K., B.J.K., and M.H. drafted the manuscript, and all other authors revised it critically. The final manuscript has been read and approved by all authors.
The establishment of synthesis and quality control for in-house production of [177Lu]Lu-RM2 was supported by Life Molecular Imaging GmbH (LMI; formerly Piramal Imaging). The precursor RM2-TFA was provided by LMI.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The need for a formal review of this retrospective study was waived by the Ethical Committee of the University of Rostock (file no. A 2018-0240).
Written informed consent to undergo therapy with subsequent follow-up was obtained from all patients included in the study.
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