2026-08-16 | [177Lu]Lu-DOTA-TATE plus long-acting octreotide in patients with newly diagnosed, advanced, grade 2-3, gastroenteropancreatic neuroendocrine tumours: preplanned and post-hoc efficacy analyses from the randomised, phase 3 NETTER-2 trial.
In the phase 3 NETTER-2 study, first-line [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) significantly improved progression-free survival in patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Median progression-free survival was 22·8 months (95% CI 19·4-not estimable [NE]) with 177Lu-DOTATATE vs 8·5 months (7·7-13·8) in the control arm. Here, we report subgroup analyses, including preplanned assessments of efficacy by NET grade (G) and site of origin; further post-hoc analyses are reported in the main text. In this open-label, parallel-group study, patients from nine countries were randomised 2:1 to receive four cycles of 177Lu-DOTATATE plus octreotide long-acting repeatable (LAR) 30 mg every 8 weeks then octreotide LAR 30 mg every 4 weeks, or high-dose octreotide LAR 60 mg every 4 weeks. The primary endpoint (progression-free survival) was previously reported. Tumours were assessed at baseline, week 16, week 24, then every 12 weeks until disease progression or death. Preplanned subgroup analyses used blinded independent centrally reviewed data. The study is registered with ClinicalTrials.gov, NCT03972488, and is completed. Between Jan 22, 2020, and Oct 13, 2022, 261 patients were screened; 35 were excluded due to screen failure, and 226 were randomised. 177Lu-DOTATATE (n = 151) reduced risk of disease progression/death vs control (n = 75) regardless of NET grade/origin (hazard ratio [95% CI]: G2 NET 0·31 [0·18-0·53]; G3 NET 0·27 [0·14-0·49]; pancreatic NET 0·34 [0·20-0·56]; gastrointestinal NET 0·23 [0·12-0·46]). Median progression-free survival in months (95% CI) with 177Lu-DOTATATE was: G2 NET 29·0 (21·8-NE); G3 NET 22·2 (13·9-27·8); pancreatic NET 19·4 (16·6-24·9); gastrointestinal NET NE (22·6-NE). 177Lu-DOTATATE improved objective response rate vs control regardless of NET grade/origin. These findings support the use of first-line 177Lu-DOTATATE for patients with advanced, well-differentiated, higher grade 2-3 (Ki67 ≥10% and ≤55%), somatostatin receptor-positive GEP-NETs, and for whom chemotherapy is not considered the most appropriate treatment option, regardless of NET grade (2/3) or origin (pancreas/gastrointestinal). Advanced Accelerator Applications, a Novartis Company.
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2026-07-24 | Expanded GEP-NET organoid culture for personalized therapy evaluation.
Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are a rare subset of cancers with increasing incidence. Due to their slow growth and lack of targetable mutations, the identification of effective treatments remains limited. One reason behind this stagnation is the lack of applicable, accurate study models. One solution is patient tumor organoids (PTOs) that maintain tumor characteristics and can scale for high throughput assays. In this study, PTOs were generated from 35 tumors of pancreatic, small intestinal, and gastric origin, obtained from 17 patients. Important subtypes including hormone functional and MEN1/VHL mutant GEP-NETs are represented, with each demonstrating growth in culture while maintaining GEP-NET immunohistochemistry and genomic characteristics. Half of G2/G3 tumors (10 of 20) could be cultured past passage 6, whereas G1 tumors (n = 15) were capable of growth until passage 4. Therapeutic targeting of the PTOs displayed both tissue-origin and grade-based response to standard of care and investigational therapies while maintaining patient tumor sensitivity and resistance. Last, a successful PTO xenograft model was developed from one PTO line. This study describes GEP-NET organoid development that demonstrates feasibility for expansion, enabling their use for translational investigations.
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2026-07-16 | Primary tumor resection prior to peptide receptor radionuclide therapy is associated with improved survival in metastatic gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis.
The role of primary tumor resection (PTR) in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing peptide receptor radionuclide therapy (PRRT) remains uncertain. This meta-analysis evaluated whether PTR prior to PRRT is associated with improved survival outcomes compared to PRRT alone. MEDLINE, Embase, and the Cochrane Library were searched through November 19, 2024 (PROSPERO CRD42024605382). Eligible studies included metastatic GEP-NET patients treated with PRRT, with or without prior PTR. Data extraction was performed independently in duplicate following PRISMA guidelines. Risk of bias was assessed using the QUIPS tool. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were pooled using random-effects models. Five observational studies, involving 1,186 patients (649 with PTR before PRRT; 537 receiving PRRT alone), met the inclusion criteria. PTR prior to PRRT was associated with longer PFS (HR, 0.62; 95% CI, 0.42-0.91; I² = 45%) and OS (HR, 0.46; 95% CI, 0.33-0.65; I² = 0%). Given the observational design, confounding by indication and potential immortal-time bias were the primary sources of bias, though the overall risk was rated low to moderate. PTR before PRRT was associated with longer PFS and OS in metastatic, somatostatin receptor-positive GEP-NETs. These findings may indicate an association, but the low certainty of the observational evidence limits their interpretability. Future well-designed studies are required to confirm or refute this observation.
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2026-07-15 | Dosimetry in 177Lu-PRRT for Neuroendocrine Tumors: Current Concepts, Clinical Relevance and Future Perspectives.
Background: Neuroendocrine tumors-are relatively rare but increasingly diagnosed malignancies originating from diffuse neuroendocrine cells, most commonly affecting the gastroenteropancreatic system. Due to their long asymptomatic development and low incidence, pose a diagnostic and therapeutic challenge for physicians. Recently, the role of nuclear medicine has been growing not only in the diagnostic stage but also in treatment. Systemic radionuclide therapy using somatostatin analogs labelled with the radioisotope lutetium-177 is becoming increasingly common in patients with advanced-stage disease. Currently, most patients receive a standard activity of therapeutic radiopharmaceuticals. Recent clinical studies provide increasing evidence of a close relationship between the absorbed radiation dose in pathological lesions and the therapeutic effect of radioisotope therapy. Internal dosimetry is used to measure the doses of ionising radiation absorbed by the patient after administration of the radiopharmaceutical. The lack of individual internal dosimetry prior to therapy means that only a small fraction of patients receive optimal doses of radioactivity, which is markedly different from external beam radiotherapy planning. Methods: A narrative literature review was conducted using the PubMed/MEDLINE and Embase databases, focusing primarily on publications from the last years. The search strategy included combinations of keywords related to peptide receptor radionuclide therapy and dosimetry, such as "Lutetium-177", "neuroendocrine tumors", "dosimetry", "PRRT", "systemic radionuclide therapy" and "artificial intelligence". Particular emphasis was placed on recent prospective clinical studies, multicenter investigations, systematic reviews and consensus documents published by major nuclear medicine societies, including the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). Seminal earlier publications considered essential for understanding the development of dosimetry concepts and clinical implementation were also included. Results: This study confirms the existence of a clinically significant dose-response relationship in 177Lu-PRRT. Higher absorbed doses to tumour lesions are associated with longer progression-free survival. The lack of individualized internal dosimetry prior to therapy means that only a small proportion of patients receive optimal radiation doses. Simplified dosimetric approaches with a reduced number of imaging time points, together with emerging artificial intelligence-based tools, appear promising for reducing the complexity of the dosimetry process. Conclusions: The aim of this study was to analyse the current literature on the role of internal dosimetry in the treatment of neuroendocrine tumors using the radioisotope lutetium-177. Available data support the clinical relevance of individualized dosimetry and highlight its potential to optimize both therapeutic efficacy and treatment safety.
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2026-07-13 | Targeted Radionuclide Therapy: Current Landscape and Combination Approaches to Improve Oncology Outcomes.
Targeted radionuclide therapy (TRT) is an emerging modality in oncology that delivers internal radiation specifically to tumor sites. It typically consists of a particle-emitting radionuclide, a linking complex with a chelator for securely binding radionuclides to targeting molecules, and a binding moiety of targets expressed on tumor cells. Early clinical results have been promising, with several TRT agents approved for treating various cancers, including prostate cancer and gastroenteropancreatic neuroendocrine tumors, or their microenvironment. However, most patients eventually relapse following TRT monotherapy, leaving room to further improve patient outcomes. Combination strategies could be beneficial to improve therapeutic index, enhance cytotoxic effects, or modulate tumor target expression; promising preclinical data have led to early-phase clinical trials. This review provides a concise overview of physical and chemical properties of commonly used β- and α-emitting radionuclides and a forward-looking rationale for combination regimens of TRT and other therapeutic modalities, such as hormone therapy, DNA damage repair inhibitors, immunotherapy, chemotherapy, external beam radiation therapy, and other combinations. We discuss the preclinical rationale, available clinical data, and ongoing key clinical trials with TRT combination therapy. Additionally, we highlight future perspectives including emerging radionuclides and prognostic and predictive biomarkers to optimize TRT combination therapy.
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