Abstract
242300
Introduction: Despite the great results of PSMA-targeted therapy, there are a number of patients who do not show sufficient PSMA expression initially or during the course of the disease. The gastrin releasing peptide receptor (GRPr) can be an alternative molecular target for diagnosis and therapy in some of these patients [1, 2]. Recently, a new GRPr ligand, AMTG([α-methyl-Trp8]RM2, has been introduced and already used clinically as 68Ga-labeled diagnostic [3], which is expected to have higher in vivo stability in human serum over a longer period of time. This might have a beneficial effect on the achievable tumor doses, when labeling the ligand with a beta-emitting radiometal.Therefore, this study aimed to assess biodistribution and absorbed doses for organs at risk and tumor lesions for [177Lu]Lu-AMTG administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who presented insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of PSMA-therapy.
Methods: 4 patients suffering from mCRPC, without adequate treatment options for approved therapies (mean age of 67 y (range: 52 … 69 y)), who showed sufficient uptake in previous GRPr-PET/CT were recruited for therapy. The mean administered activity was 7.5 ± 0.2 GBq. 2 patients received 2 or 3 treatment cycles. The therapies were conducted as individual treatments in accordance with the German Medicines Act (AMG, §13[2b]) and confirmed by an interdisciplinary tumor board. For dosimetry, patients underwent quantitative SPECT/CT imaging (Siemens Symbia T6 or GE Discovery 870 CZT) of the upper and lower abdomen at approximately 1 h, 24 h, 48 h and 72 h p.i. along with blood sampling. Absorbed doses in kidneys, pancreas, liver, spleen, red bone marrow, and 34 tumor lesions were calculated from SPECT/CT data according to MIRD dosimetry scheme and the respective EANM dosimetry guidelines.
Results: The therapy was well-tolerated by all patients and no treatment-associated side effects have been observed. A rapid uptake in tumor lesions and the pancreas has been observed within the first hour after injection. Mean absorbed dose rates (doses) in the considered organs at risk were 0.26±0.11 Gy/GBq (1.95±0.67 Gy) in the pancreas, 0.24±0.08 Gy/GBq (1.75±0.50 Gy) in the kidneys, 0.05±0.01 Gy/GBq (0.39±0.08 Gy) in the liver, 0.04±0.01 Gy/GBq (0.32±0.11 Gy) in the spleen and 0.03±0.02 Gy/GBq (0.25±0.13 Gy) for the red bone marrow. In direct comparison, the organ absorbed doses when using the parent peptide RM2 were 1.08 ± 0.44 Gy/GBq in the pancreas and 0.35 ± 0.14 Gy/GBq in the kidneys [2].
In contrast to the rapid washout from the organs at risk, the binding of AMTG was more stable in tumor tissue. This was reflected in effective half-lives of 45.5 h and 62.8 h in soft tissue and bone metastases, respectively. The mean dose rates (doses) for tumor lesions were 1.8±0.9 Gy/GBq (13.4±6.7 Gy) and 3.1±0.8 Gy/GBq (20.6±8.3 Gy) for soft tissue and bone lesions, respectively.
Conclusions: [177Lu]Lu-AMTG has advantageous properties in terms of biodistribution and dosimetry, which predestine it for therapeutic use. In particular, its rapid washout from the pancreas, which is considered the main organ at risk, and the resulting low dose exposure clearly distinguish it from its parent peptide RM2. In contrast, it binds significantly longer in tumor tissue and therapeutically relevant doses can be achieved. This advantageous profile also allows the use of higher activities or more biologically effective radionuclides to increase tumor control probability.
References[1] Mansi R et al. Eur J Nucl Med Mol Imaging. 2011 Jan;38(1):97-107[2] Kurth J et al. Eur J Nucl Med Mol Imaging. 2020 Jan;47(1):123-135.[3] Koller L et al. J Nucl Med. 2023: jnumed.123.265771.
