First-in-human study of dosimetry, safety and efficacy for [177Lu]Lu-P15-073: a novel bisphosphonate-based radioligand therapy (RLT) agent for bone metastases.

PURPOSE: Bisphosphonates are pivotal in managing bone tumors by inhibiting bone resorption. This study investigates the therapeutic potential of [177Lu]Lu-P15-073, a novel bisphosphonate, for radioligand therapy (RLT) in bone metastases. METHODS: Ten patients (age 35 to 75) with confirmed bone metastases underwent therapy with a single dose of [177Lu]Lu-P15-073 (1,225 ± 84 MBq, or 33 ± 2 mCi). Prior to treatment, bone metastases were verified via [99mTc]Tc-MDP bone scans. Serial planar whole-body scans monitored biodistribution over a 14-day period. Dosimetry was assessed for major organs and tumor lesions, while safety was evaluated through blood biomarkers and pain scores. RESULTS: Serial planar whole-body scans demonstrated rapid and substantial accumulation of [177Lu]Lu-P15-073 in bone metastases, with minimal uptake in blood and other organs. The absorbed dose in the critical organ, red marrow, was measured at (0.034 ± 0.010 mSv/MBq), with a notably low normalized effective dose (0.013 ± 0.005 mSv/MBq) compared to other 177Lu-labeled bisphosphonates. Persistent high uptake in bone metastases was observed, resulting in elevated tumor doses (median 3.12 Gy/GBq). Patients exhibited favorable tolerance to [177Lu]Lu-P15-073 therapy, with no new instances of side effects. Additionally, 87.5% (7/8) of patients experienced a significant reduction in pain scale (numerical rating scale, NRS, from 5.1 ± 2.3 to 3.0 ± 1.8). The tumor-background ratio (TBRmean) of [99mTc]Tc-MDP correlated significantly with [177Lu]Lu-P15-073 uptake (P < 0.01), indicating its potential for prediction of absorbed dose. CONCLUSIONS: This study demonstrates the safety, dosimetry, and efficacy of a single therapeutic dose of [177Lu]Lu-P15-073 in bone metastases. The treatment was well-tolerated with no severe adverse events. These findings suggest that [177Lu]Lu-P15-073 holds promise as a novel RLT agent for bone metastases.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). METHODS: Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. RESULTS: Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. CONCLUSION: [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. TRIAL REGISTRATION: 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05603559 .

Extended therapy with [177Lu]Lu-PSMA-617 in responding patients with high-volume metastatic castration-resistant prostate cancer.

PURPOSE: The currently used scheme for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC) consists of 4-6 cycles of 6.0-7.4 GBq [177Lu]Lu-PSMA-617 each. This standard treatment scheme has proved safe and effective resulting in objective response in most patients with no significant toxicity. Many patients, however, show high-volume residual tumor burden after the sixth cycle and may benefit from treatment continuation. Extended treatment with additional cycles has been withheld due to concerns on potential increased toxicity. METHODS: Twenty-six patients with high-volume residual tumor burden (according to CHAARTED) after standard RLT with [177Lu]Lu-PSMA-617 and no alternative treatment option received additional RLT cycles reaching a median of 10 (range 7-16) cycles with a mean activity of 7.4 ± 0.9 GBq per cycle. Response assessment with [68Ga]Ga-PSMA-11 PET/CT was done every 2-3 cycles or if disease progression was clinically suspected or based on change in PSA value (according to the PCWG3 criteria). Toxicity was measured using routine blood work up including blood counts, liver and renal function, and was graded according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. RESULTS: Further PSA decline of 33 ± 28% during the extended treatment was observed in 21/26 (81%) patients, whereas 5/26 (19%) patients showed a PSA increase; correspondingly in 11/21 patients with an initial response (PR or SD) to extended cycles, treatment was discontinued due to progressive disease, whereas six (23%) patients achieved low-volume residual disease. Two (8%) patients died without showing progression, and two (8%) patients are still under therapy. The median progression-free survival was 19 (95% CI: 15-23) months, and the overall survival was 29 (95% CI: 18-40) months. Grade ≥ 3 hematological toxicities occurred in 4/26 (15%) patients during treatment extension, and nephrotoxicity (grade ≥ 3) was observed in 1/26 (4%) patient during the follow-up. CONCLUSION: Extended radioligand therapy is a feasible treatment option in patients with high-volume residual tumor after the completion of standard treatment with six cycles of [177Lu]Lu-PSMA-617. Improved survival and the acceptable safety profile warrant further investigation of the concept of additional cycles in selected patients.

Renal Disturbances during and after Radioligand Therapy of Neuroendocrine Tumors-Extended Analysis of Potential Acute and Chronic Complications.

Neuroendocrine tumors (NEN) are a group of neoplasms that arise from hormonal and neural cells. Despite a common origin, their clinical symptoms and outcomes are varied. They are most commonly localized in the gastrointestinal tract. Targeted radioligand therapy (RLT) is a treatment option which has proven to be successful in recent studies. However, the possible outcomes and true safety profile of the treatment need to be fully determined, especially by new, more sensitive methods. Our study aimed to present an extended analysis of acute and chronic renal complications during and after radioligand therapy using, for the first time in the literature, innovative and complex renal parameters. Forty patients with neuroendocrine tumors underwent four courses of radioligand therapy with [177Lu]Lu-DOTATATE or [177Lu]Lu/[90Y]Y-DOTATATE. Radioisotopes were administrated in intervals of 8-12 weeks, with concurrent intravenous nephroprotection. New detailed and sensitive renal parameters were used to determine the renal safety profile during and after radioisotope therapy for standard treatment of NEN. During the first and fourth courses of RLT, no change in the glomerular filtration rate (GFR) was observed. However, long-term observations one year after the treatment showed a 10% reduction in the GFR. During the first course of treatment, the fractional urea and calcium excretions increased, while the fractional potassium concentration decreased. The fractional calcium excretion remained highly increased in long-term observations. Decreases in urine IL-18, KIM-1 and albumin concentrations were observed during RLT. The concentrations of IL-18 and KIM-1 remained low even a year after therapy. The ultrasound parameters of renal perfusion changed during treatment, before partially returning to the baseline one year after therapy, and were correlated with the biochemical parameters of renal function. A permanent increase in diastolic blood pressure was correlated with the decrease in the GFR observed during the study. In this innovative and complex renal assessment during and after RLT, we found a permanent 10% per year decrease in the GFR and noticeable disturbances in renal tubule function. The diastolic blood pressure also increased.

Response and outcome of liver metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing 177Lu-PSMA-617 radioligand therapy.

PURPOSE: Little is known about the efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) against liver metastases of metastatic castration-resistant prostate cancer (mCRPC). We retrospectively analyzed efficacy-related outcomes of 177Lu-PSMA-617 RLT in this setting and potential predictors of those outcomes. METHODS: Twenty-eight consecutive mCRPC patients with liver metastases given 177Lu-PSMA-617 RLT were analyzed retrospectively. Their planned regimen was 4-6 cycles at 6 ± 2-week intervals; the mean activity/cycle was 6.5 ± 0.5 GBq. Hepatic response was determined by modified positron emission tomography response criteria in solid tumors; association of such response with overall survival (OS) was tested, as were relationships of the selected patient, disease, and treatment characteristics with hepatic progression-free survival (PFShep) and OS. Survival analyses used Kaplan-Meier curves, log-rank test at p < 0.05 significance, and Cox proportional-hazards modeling. RESULTS: Median (minimum-maximum) follow-up was 37.5 (2.3-50.6) months. In liver metastases, complete or partial response was observed in 6 patients (21%) each, and stable disease in 1 (4%), for hepatic disease control in 46%. Overall, median (95% confidence interval) PFShep was 5.7 (2.2-9.2) months, and OS, 11.7 (3.0-20.4) months. Patients with hepatic disease control did not reach the median OS, while those with hepatic progressive disease had median OS (95% confidence interval) of 6.4 (1.6-11.1) months. In multivariate analysis, hepatic disease control by 177Lu-PSMA-617 RLT was significantly independently associated with OS, as was a prostate-specific antigen decline of ≥ 50% after 2 RLT cycles, and good baseline performance status (Eastern Cooperative Oncology Group 0-1). Hepatic tumor burden (≤ 25% vs. > 25% of liver volume) had no apparent relationship with hepatic tumor response, PFShep, or OS. CONCLUSION: 177Lu-PSMA-617 RLT frequently controlled liver metastases, resulting in long PFShep and significantly improved OS. Hepatic tumor burden appeared to lack any relationship with treatment efficacy, supporting 177Lu-PSMA-617 RLT of late-stage/end-stage mCRPC with liver metastases.

Synthesis and evaluation of novel radioiodinated PSMA targeting ligands for potential radiotherapy of prostate cancer.

Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l-tyrosine and l-glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with 125I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC50 = 1-13 nM). In vitro cell uptake studies demonstrated that compounds containing an l-tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l-tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [125I]8 and [125I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [125I]19a/19b and [125I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [125I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2-3-fold lower uptake in the liver and blood than that observed for [125I]MIP-1095. [125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.

First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

PURPOSE: This translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of 177Lu-EB-PSMA-617 in comparison to 177Lu-PSMA-617 in patients with mCRPC. METHODS: Following institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80-1.1 GBq (21.5-30 mCi) of 177Lu-EB-PSMA-617, then underwent serial whole-body planar and SPECT/CT imaging at 2, 24, 72, 120 and 168 h. The other five patients accepted intravenous injection of 1.30-1.42 GBq (35-38.4 mCi) 177Lu-PSMA-617, then underwent the same imaging procedures at 0.5, 2, 24, 48, and 72 h. All patients were evaluated by 68Ga-PSMA-617 PET/CT before and one month after the treatment. Dosimetry evaluation was compared in both patient groups. RESULTS: When the bone metastasis tumors with comparable baseline SUVmax in the range of 10.0-15.0 were selected from the two groups for comparison, the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617. Imaging dose of 177Lu-EB-PSMA-617 treatment showed significant decrease of 68Ga-PSMA-617 uptake within a month, which was not observed in patients imaged with 177Lu-PSMA-617 (SUV change: -32.43 ± 0.14% vs. 0.21 ± 0.37%; P = 0.002). 177Lu-EB-PSMA-617 also had higher absorbed doses in the red bone marrow and kidneys than 177Lu-PSMA-617 (0.0547 ± 0.0062 vs. 0.0084 ± 0.0057 mSv/MBq for red bone marrow, P < 0.01; 2.39 ± 0.69 vs. 0.39 ± 0.06 mSv/MBq for kidneys, P < 0.01). CONCLUSION: This first-in-human study demonstrated that 177Lu-EB-PSMA-617 had higher accumulation in mCRPC and that low imaging dose appears to be effective in treating tumors with high 68Ga-PSMA-617 uptakes. Elevated uptakes of 177Lu-EB-PSMA-617 in kidneys and red bone marrow were well tolerated at the administered low dose. Further investigations with increased dose and frequency of administration are warranted.

Comparison of 18F-DCFPyL and 68Ga-PSMA-11 for 177Lu-PSMA-617 therapy patient selection.

Purpose: 68Ga-PSMA-11 is recommended for the selection of patients for treatment in the package insert for 177Lu-PSMA-617. We aimed to compare imaging properties and post-treatment outcomes from radioligand therapy (RLT) of patients selected with 68Ga-PSMA-11 and 18F-DCFPyL. Methods: We retrospectively evaluated 80 patients undergoing PSMA RLT, who had pretreatment imaging using either 68Ga-PSMA-11 or 18F-DCFPyL. For both groups, we compared the biodistribution and lesion uptake and the PSA response to treatment. Results: Both agents had comparable biodistribution. Patients initially imaged with 18F-DCFPyL had a higher PSA response (66% vs. 42%), and more patients had a PSA50 response (72% vs. 43%) compared to patients imaged with 68Ga-PSMA-11. Conclusion: 18F-DCFPyL and 68Ga-PSMA-11 had comparable biodistribution and lesion uptake. Patients imaged with 18F-DCFPyL demonstrated clinical benefit to PSMA RLT comparable to those imaged with 68Ga-PSMA-11, and either agent can be used for screening patients.

Angiogenic biomarkers of response to treatment with peptide receptor radionuclide therapy in neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Matched-pair analysis of mCRPC patients receiving 177Lu-labeled PSMA-targeted radioligand therapy in a 4-week versus 6-week treatment interval.

BACKGROUND: The optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals. RESULTS: A PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups. CONCLUSIONS: Intensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome.

Analysis of Molecular Imaging and Laboratory Baseline Biomarkers in PSMA-RLT: Whole-Body Total Lesion PSMA (TLP) Predicts Overall Survival.

The aim of this retrospective study was to identify pre-therapeutic predictive laboratory and molecular imaging biomarkers for response and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Pre-therapeutic laboratory and [68Ga]Ga-PSMA-11 PET/CT data of n = 102 mCRPC patients receiving [177Lu]Lu-PSMA-617 RLT within a prospective registry (REALITY Study, NCT04833517) were analyzed including laboratory parameters such as alkaline phosphatase (ALP), prostate-specific antigen (PSA), gamma glutamyl transferase (GGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), neuron specific enolase (NSE), hemoglobin (Hb), and imaging parameters such as maximum standardized uptake value of the tumor lesions (SUVmax), the mean standardized uptake value of all tumor lesions (SUVmean), the whole-body molecular tumor volume (MTV), and the whole-body total lesion PSMA (TLP). Mann-Whitney U test, univariate and multivariable Cox-regression were performed to test for association of the parameters with response and OS. The SUVmean of all lesions was significantly different between responders and non-responders (SUVmean responders 8.95 ± 2.83 vs. non-responders 7.88 ± 4.46, p = 0.003), whereas all other tested biochemical and imaging parameters did not reveal significant differences. Hb and the molecular imaging parameters MTV and TLP showed a significant association with OS (p = 0.013, p = 0.005; p = 0.009) in univariant Cox regression; however, only TLP remained significant in multivariable analysis (Hazard ratio 1.033, p = 0.009). This study demonstrates a statistically significant association between the quantitative PET/CT imaging parameter SUVmean and PSA response, as well as between the baseline TLP and OS of mCRPC patients undergoing RLT.

Tumor Sink Effect with Prostate-Specific Membrane Antigen-Targeted Theranostics in Patients with Metastatic Castration-Resistant Prostate Cancer: Intra-Individual Evaluations.

"Tumor sink effects", decreased physiological uptake of radiopharmaceuticals due to sequestration by a tumor, may impact radioligand therapy (RLT) toxicity and dosing. We investigated these effects with prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals in the healthy organs-at-risk (the parotid glands, kidneys, liver, and spleen) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively performed three intra-individual comparisons. First, we correlated changes from baseline to post-RLT (after two 177-lutetium (177Lu)-PSMA-617 cycles) in total lesional PSMA (∆TLP) and organ mean standardized uptake values (∆SUVmean). Second, in 25 RLT responders, we compared the organ SUVmean post-RLT versus that at baseline. Lastly, we correlated the baseline TLP and organ SUVmean. Data were acquired via 68-gallium-PSMA-11 positron emission tomography before the first and after the second 177Lu-PSMA-617 cycle. In the parotid glands and spleen, ∆TLP and ∆SUVmean showed a significant inverse correlation (r = -0.40, p = 0.023 and r = -0.36, p = 0.042, respectively). Additionally, in those tissues, the median organ SUVmean rose significantly from baseline after the response to RLT (p ≤ 0.022), and the baseline TLP and SUVmean were significantly negatively correlated (r = -0.44, p = 0.01 and r = -0.42, p = 0.016, respectively). These observations suggest tumor sink effects with PSMA-targeted radiopharmaceuticals in the salivary glands and spleen of patients with mCRPC.

PSMA-targeted therapy for non-prostate cancers.

Radioligand therapy (RLT) agents are demonstrating a crucial role in the clinical approach to aggressive malignancies such as metastatic castrate-resistant prostate cancer (m-CRPC). With the recent FDA approval of prostate-specific membrane antigen (PSMA)-targeted RLT for m-CRPC, the field has broadened its gaze to explore other cancers that express PSMA in the tumor parenchyma or tumor neovasculature. In this review article, we discuss current progress in the clinical use of PSMA RLTs in non-prostate cancers such salivary gland cancers, renal cell carcinoma, high grade glioma, and soft tissue sarcoma. We highlight early reports in small case series and clinical trials indicating promise for PSMA-targeted RLT and highlighting the importance of identifying patient cohorts who may most benefit from these interventions. Further study is indicated in non-prostate cancers investigating PSMA RLT dosimetry, PSMA PET/CT imaging as a biomarker, and assessing PSMA RLT safety and efficacy in these cancers.

Intermittent Radioligand Therapy with 177Lu-PSMA-617 for Oligometastatic Castration-Resistant Prostate Cancer.

177Lu-PSMA-617 radioligand therapy (177Lu-PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC) currently consists of 4-6 cycles of 6.0-7.4 GBq of 177Lu-PSMA-617 each every 6-8 weeks. While safety and efficacy could be demonstrated in larger prospective trials irrespective of the tumor burden at 177Lu-PSMA RLT initiation, increased renal absorbed doses due to a reduced tumor sink effect in early responding, oligometastatic mCRPC patients pose difficulties. Response-adapted, dose distributing, intermittent treatment with up to six cycles has not been routinely performed, due to concerns about the potential loss of disease control. Treatment was discontinued in 19 early-responding patients with oligometastatic tumor burden after two (IQR 2-3) cycles of 177Lu-PSMA-RLT and 6.5 ± 0.7 GBq per cycle and resumed upon 68Ga-PSMA-11-PET/CT-based progression (according to the PCWG3 criteria). Subsequent treatment breaks were imposed if a PSMA-based imaging response could be achieved. A total of five (IQR 3-6) cycles reaching a cumulative activity of 32 ± 11 GBq were applied. A routine blood work-up including blood counts and liver and renal function was measured throughout the 177Lu-PSMA-RLT and follow-up to grade toxicity according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. In total, treatment-free periods of 9 (IQR 6-17) cumulative months and the application of 177Lu-PSMA-RLT cycles over 16 (IQR 9-22) months could be achieved. Fifteen (84%) patients responded to subsequent cycles after the first treatment break and in 7/19 (37%) patients, intermittent 177Lu-PSMA-RLT consisted of ≥2 treatment breaks. The median PFS was 27 months (95% CI: 23-31) and overall survival was 45 months (95% CI: 28-62). No grade ≥3 hematological or renal toxicities could be observed during the 45 ± 21 months of follow-up. The cumulative mean renal absorbed dose was 16.7 ± 8.3 Gy and 0.53 ± 0.21 Gy/GBq. Intermittent radioligand therapy with 177Lu-PSMA-617 is feasible in early-responding patients with oligometastatic disease. A late onset of progression after subsequent cycles and the absence of significant toxicity warrants further investigation of the concept of intermittent treatment in selected patients.

Novel Generation of FAP Inhibitor-Based Homodimers for Improved Application in Radiotheranostics.

Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides 177Lu and 225Ac. This was improved with the dimer DOTAGA.(SA.FAPi)2, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)2 and DOTAGA.Glu.(FAPi)2. were synthesized and quantitatively radiolabeled with 68Ga, 90Y, 177Lu and 225Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [225Ac]Ac-DOTAGA.Glu.(FAPi)2 in PBS. In vitro affinity studies resulted in subnanomolar IC50 values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [natLu]Lu-DOTAGA.Glu.(FAPi)2. In a first proof-of-principle patient study (medullary thyroid cancer), [177Lu]Lu-DOTAGA.Glu.(FAPi)2 was compared to [177Lu]Lu-DOTAGA.(SA.FAPi)2. High uptake and long tumor retention was observed in both cases, but [177Lu]Lu-DOTAGA.Glu.(FAPi)2 significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)2 showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [225Ac]Ac-DOTAGA.Glu.(FAPi)2 appear promising for translational application in patients.

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still "Lutathera orphans", and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.

Individualization of Radionuclide Therapies: Challenges and Prospects.

The article presents the problems of clinical implementation of personalized radioisotope therapy. The use of radioactive drugs in the treatment of malignant and benign diseases is rapidly expanding. Currently, in the majority of nuclear medicine departments worldwide, patients receive standard activities of therapeutic radiopharmaceuticals. Intensively conducted clinical trials constantly provide more evidence of a close relationship between the dose of radiopharmaceutical absorbed in pathological tissues and the therapeutic effect of radioisotope therapy. Due to the lack of individual internal dosimetry (based on the quantitative analysis of a series of diagnostic images) before or during the treatment, only a small fraction of patients receives optimal radioactivity. The vast majority of patients receive too-low doses of ionizing radiation to the target tissues. This conservative approach provides "radiation safety" to healthy tissues, but also delivers lower radiopharmaceutical activity to the neoplastic tissue, resulting in a low level of response and a higher relapse rate. The article presents information on the currently used radionuclides in individual radioisotope therapies and on radionuclides newly introduced to the therapeutic market. It discusses the causes of difficulties with the implementation of individualized radioisotope therapies as well as possible changes in the current clinical situation.

[177Lu]Lu-PSMA-617 (PluvictoTM): The First FDA-Approved Radiotherapeutical for Treatment of Prostate Cancer.

In March 2022, [177Lu]Lu-PSMA-617 (PluvictoTM) was approved by the FDA for the treatment of prostate cancer patients. Until now, the approval has been limited to patients with PSMA-positive metastatic castration-resistant prostate cancer who have previously received other therapy options (such as inhibition of the androgen receptor pathway and taxane-based chemotherapy). [177Lu]Lu-PSMA-617, which combines a PSMA-specific peptidomimetic with a therapeutical radionuclide, is used in a radioligand therapy that selectively delivers ionizing radiation to tumor cells, causing their death, while sparing the surrounding healthy tissue. In numerous clinical trials, the efficacy of [177Lu]Lu-PSMA-617 was demonstrated.

177Lu-PSMA-I&T Radioligand Therapy for Treating Metastatic Castration-Resistant Prostate Cancer: A Single-Centre Study in East Asians.

Purpose: There is increasing evidence for convincing efficacy and safety of 177Lu-labled prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) for metastatic castration-resistant prostate cancer (mCRPC). However, data are not available regarding the feasibility of 177Lu-labled PSMA-targeted RLT in East Asians. The present study summarized the first experience with 177Lu-PSMA-I&T therapy for mCRPC in China. Methods: Forty consecutive patients with mCRPC were enrolled from December 2019 to September 2021. Eligible patients received 177Lu-PSMA-I&T RLT at intervals of 8-12 weeks. Toxicity was assessed based on standardized physicians' reports and the Common Toxicity Criteria for Adverse Events criteria. Response to PRLT was evaluated according to the changes of prostate specific antigen (PSA) response and imaging response. Quality of life (QOL), Karnofsky performance status (KPS) and pain (visual analogue scale, VAS) were also evaluated. The impacts of baseline parameters on the therapeutic effects were explored by univariate and multivariate logistic regression analyses. Results: All patients underwent a total of 86 cycles of 177Lu-PSMA-I&T (range: 1-5 cycles) with dosages of 3.70-14.43GBq per cycle, with a median of 8 months followed up. Six patients (15%) developed mild reversible xerostomia during follow-up, and 28 patients (70%) experienced grade 1-4 bone marrow dysfunction. Changes in PSA were assessed after therapy, accompanied by the partial response (PR) in 25 patients (62.5%), the stable disease (SD) in 5 patients (12.5%), and the progressive disease (PD) in 10 patients (25%), respectively. QOL, KPS (%) and VAS scores were improved significantly due to treatment (P<0.05). Overweight and elevated AST, ALP, and LDH were associated with poor outcomes. Conclusions: 177Lu-PSMA-I&T achieves the favourable response and well tolerance in mCRPC, which associates with not only PSA decline but also with tumor remission including lymphadenopathy and bone metastasis. We also find that patients with overweight and high AST, ALP, and LDH should be cautious to undergo the PRLT. Large-cohort studies are warranted to confirm the initial findings and elucidate the survival benefit of the treatment.

177Lu-PSMA-RLT of metastatic castration-resistant prostate cancer: limitations and improvements.

The prevalence of metastatic castration-resistant prostate cancer (mCRPC) is increasing, and its prognosis is often poor. As a highly expressed target in mCRPC, prostate-specific membrane antigen (PSMA) is very attractive for its diagnosis and treatment. When the efficacy of chemical therapy is limited, radioligand therapy (RLT)-based on Lutetium-177 (177Lu)-PSMA has received more research as an emerging treatment. To date, most published related studies have proven this method is effective and safe. However, about 1/3 of mCRPC patients have not benefited from 177Lu-PSMA-RLT. The underlying mechanism of this phenomenon remains unclear. So based on the comprehensive research in recent years, this article proposes the possible reasons, including tumor lesions, PSMA heterogeneity, differences in DNA repair defects, and accelerated repopulation. Combining with the existing experience to give suggestions to improve the treatment efficacy, benefit more mCRPC patients.