Radiolabeled somatostatin receptor (sstr) antagonists have shown in vivo higher uptake in sstr-expressing tumors than agonists. In this pre-clinical study the sstr2-antagonist OPS201 (DOTA-JR11; DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2]) labeled with ¹⁷⁷Lu, ⁹⁰Y and ¹¹¹In was compared with the sstr2-agonist ¹⁷⁷Lu-DOTA-TATE. Methods: Biodistribution, pharmacokinetics, single-photon emission computed tomography/computed tomography (SPECT/CT) and dosimetry studies were performed to assess the bioequivalence of all radiotracers. Use of escalated peptide mass and nephroprotective agents were systematically investigated. Results: The tumor residence time was 15.6h [13.4-17.7] for ¹⁷⁷Lu-OPS201 (10 pmol) and 6.4h [5.4-7.3] for ¹⁷⁷Lu-DOTA-TATE, resulting in 2.5 times higher tumor dose for the antagonist than for the agonist (0.854 vs 0.333 mGy/MBq for a 4 cm tumor). The overall tumor-to-kidney dose ratio was approximately 24% and 32% higher for ¹⁷⁷Lu-OPS201 than for ⁹⁰Y-OPS201 and ¹⁷⁷Lu-DOTA-TATE, respectively. ¹¹¹In-OPS201 had significantly different biodistribution than ⁹⁰Y-OPS201 and is therefore not a surrogate for ⁹⁰Y-OPS201 dosimetry studies. Importantly, and in contrast to ¹⁷⁷Lu-DOTA-TATE, injection of 10, 200 and 2000 pmol of ¹⁷⁷Lu-OPS201 did not cause any relevant tumor saturation, with tumor uptake 4h post injection (p.i.): 23.9, 24.9 and 18.8 percentage of injected activity per gram of tissue (%IA/g), respectively for the antagonist (p>0.05), as compared to 17.8, 12.0 and 9.9%IA/g for the agonist (p<0.05). Increasing the peptide mass of ¹⁷⁷Lu-OPS201 from 10 to 200 pmol drastically decreased the effective dose from 0.0908 to 0.0184 mSv/MBq and also the uptake in the liver, bone marrow and all sstr2-expressing organs, thus the therapeutic index improved considerably. Lysine, Gelofusine, alone or in combination, significantly reduced the renal dose of ¹⁷⁷Lu-OPS201 compared to the control group, by 45%, 25% and 40%, respectively (p<0.05). The reduction was similar for 10 and 200 pmol, while lysine performed better than Gelofusine. Conclusion: ¹⁷⁷Lu-OPS201 exhibits higher tumor uptake, longer tumor residence time and improved tumor-to-kidney dose ratio compared to ¹⁷⁷Lu-DOTA-TATE and ⁹⁰Y-OPS201. Importantly, the mass-escalation study indicates that an optimized antagonist-mass might further improve the safety window of Peptide Receptor Radionuclide Therapy (PRRT) by reducing liver, bone marrow dose and also the effective dose. Clinical studies are warranted to confirm the efficacy and advantageous toxicity profile of ¹⁷⁷Lu-OPS201.

Purpose: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [¹⁷⁷Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. Methods: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [¹⁷⁷Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. Results: Median cumulative administered activity of [¹⁷⁷Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3–99.4), and overall response rate was 21.1% (95% CI: 9.6–37.3). Conclusion: [¹⁷⁷Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. Trial registration: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST₂) being the predominantly and most frequently expressed. PET/CT imaging with ⁶⁸Ga-labeled SST agonists, e.g., ⁶⁸Ga-DOTA-TOC (SomaKit TOC^®) or ⁶⁸Ga-DOTA-TATE (NETSPOT^®), plays an important role in staging and restaging these tumors and can identify patients who qualify and would potentially benefit from peptide receptor radionuclide therapy (PRRT) with the therapeutic counterparts ¹⁷⁷Lu-DOTA-TOC or ¹⁷⁷Lu-DOTA-TATE (Lutathera^®). This is an important feature of SST targeting, as it allows a personalized treatment approach (theranostic approach). Today, new developments hold promise for enhancing diagnostic accuracy and therapeutic efficacy. Among them, the use of SST₂ antagonists, such as JR11 and LM3, has shown certain advantages in improving image sensitivity and tumor radiation dose, and there is evidence that they may find application in other oncological indications beyond NETs and NENs. In addition, PRRT performed with more cytotoxic α-emitters, such as ²²⁵Ac, or β^- and Auger electrons, such as ¹⁶¹Tb, presents higher efficacy. It remains to be seen if any of these new developments will overpower the established radiolabeled SST analogs and PRRT with β^--emitters.

Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Methods: Inclusion criteria were histologically proven somatostatin receptor–positive metastatic malignant insulinoma and at least 2 cycles of [⁹⁰Y]Y-DOTATOC or [¹⁷⁷Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Results: Twenty-six of 32 patients with a total of 106 [⁹⁰Y]Y-DOTATOC/[¹⁷⁷Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3–107.4 mo). Before therapy, 81% (n = 21) of the patients had a hypoglycemia score of 2 and 19% (n = 5) had a score of 1. After PRRT, 81% of patients (n = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [⁹⁰Y]Y-DOTATOC/[¹⁷⁷Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0–70.2 mo). Antihypoglycemic medication reduction was achieved in 58% (n = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5–32.9 mo) and 11.7 mo (95% CI, 4.9–18.5 mo), respectively. Conclusion: To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT. Visual Abstract

Peptide receptor radionuclide therapy (PRRT) is a well-established treatment in somatostatin receptor-expressing neuroendocrine tumours (NETs). The safety and efficacy of PRRT in >79 years old patients (EP) have not been systematically investigated. All patients with inoperable/metastatic/progressive G1/G2 NET, >79 years (EP), treated with PRRT at the University Hospital of Basel between 2006 and 2018, were enrolled in this retrospective matched cohort study. Each patient was manually matched with ≥1 younger patient (YP = 60–70 years). The primary endpoint was toxicity. Toxicity (subacute, long-term) was graded according to the criteria for adverse events (CTCAE) v5.0. All toxicity grades ≥ 3, or whose delta (Δ) to baseline were ≥2, were considered significant. The odds ratio (OR) for developing toxicity was tested for non-inferiority of EP vs. YP. Clinical response to PRRT and overall survival (OS) were assessed as secondary outcome measures. Forty-eight EP and 68 YP were enrolled. Both cohorts were balanced regarding median time since diagnosis, tumour location, grading, treatment scheme, and baseline biochemical parameters, except for eGFR (EP: 61 ± 16 vs. YP: 78 ± 19; mL/min/1.73 m²). Twenty-two grade ≥ 3 or Δ ≥ 2 subacute hematotoxicities occurred in 10 EP (10.3% of cycles) and 37 in 19 YP (11.6% of cycles; p = NS). Long-term grade ≥ 3 renal toxicity occurred in 7 EP and 2 YP (p = NS). The median OS was 3.4 years (EP) vs. 6.0 years (YP), HR: 1.50 [0.75, 2.98], p = NS. PRRT is a valid therapeutic option in elderly NET patients with similar toxicity and non-inferior survival compared to matched younger patients.

Neuroendocrine tumors (NETs) pose a considerable challenge due to their increasing incidence and frequently late-stage diagnosis. The arrival of multikinase inhibitors (MKIs) into clinical practice has brought notable progress in the management of advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This review aims at exploring the impact of MKIs in reshaping the treatment landscape for advanced GEP-NETs. Current approaches in managing advanced GEP-NETs are discussed, including somatostatin analogs, surgery, peptide receptor radionuclide therapy, and approved systemic treatments such as everolimus or sunitinib. The limitations and challenges faced in treating these tumors remain significant. Here, we review the clinical evidence supporting the use of everolimus as a targeted therapy, which has demonstrated improved progression-free survival (PFS), and the need for alternative therapies. Discussions focus on the clinical effectiveness and the emerging role of both established and novel MKIs in the treatment of GEP-NETs, including recent evidence from the CABINET trial and other emerging agents such as surufatinib, axitinib, pazopanib, and lenvatinib. We explore the clinical evidence that showcases sunitinib’s and other MKIs’ effectiveness in prolonging PFS compared to placebo in advanced GEP-NETs. Recently, MKIs have shown to have a significant impact for the treatment of advanced GEP-NETs. There remain several unmet needs that must be addressed, particularly regarding optimal treatment sequencing and the development of predictive biomarkers. Ongoing research and the use of current and emerging MKIs hold great potential to advance the treatment landscape for advanced GEP-NETs significantly.