RARE DISEASE
Gastroenteropancreatic neuroendocrine neoplasm
Gastroenteropancreatic neuroendocrine neoplasm
Gastroenteropancreatic neuroendocrine neoplasm
Synonyms: GEP-NEN
Synonyms: GEP-NEN
Synonyms: GEP-NEN
Drug discovery
22
drugs
With orphan designations
Overview
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors arising from neuroendocrine cells in the gastrointestinal tract and pancreas. Classified as well-differentiated (NETs) or poorly differentiated (NECs), they range from indolent to aggressive. Functional tumors secrete hormones (e.g., insulin, gastrin), causing syndromes like carcinoid or Zollinger-Ellison, while non-functional tumors present with mass effects or metastases. Diagnosis integrates biomarkers (chromogranin A), imaging (somatostatin receptor PET), and histopathology (Ki-67 index). Treatment is multimodal, involving surgery, somatostatin analogs, peptide receptor radionuclide therapy (PRRT), targeted agents (everolimus, sunitinib), and chemotherapy (CAPTEM) based on grade, stage, and functionality [1][4][11][18].
Categories: rare endocrine diseases, rare neoplastic diseases
Research Papers
1,439 drug discovery papers about Gastroenteropancreatic neuroendocrine neoplasm, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,439 drug discovery papers about Gastroenteropancreatic neuroendocrine neoplasm, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | The Use of Adjunct Therapies with Surgery for Gastroenteropancreatic Neuroendocrine Tumors: Indications, Timing, and Outcomes.
Background/Objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare biologically heterogeneous neoplasms but with increasing incidence in recent years. Surgery remains the backbone of treatment; however, long-term recurrence is common even after curative resection. Despite expanding treatment options, the optimal perioperative integration of adjunct therapies in conjunction with surgery remains incompletely defined, as available evidence is largely retrospective and heterogeneous. This review critically synthesizes available evidence on the role of perioperative therapies in the surgical management of GEP-NENs, identifies key knowledge gaps, and highlights areas where multidisciplinary decision-making is required. Methods: A targeted narrative literature review was performed in PubMed/MEDLINE (2001-2026), supplemented by ClinicalTrials.gov and major society guidelines. Predefined search terms were used to include "gastroenteropancreatic neuroendocrine tumor", "GEP-NET", "pancreatic neuroendocrine tumor", "surgery", "palliative surgery", "neoadjuvant", "adjuvant", "PRRT", "somatostatin analogue", "chemotherapy", "targeted therapy", "immune checkpoint inhibitor", and "liver-directed therapy". Studies were selected based on relevance, with emphasis on comprehensive reviews, key clinical studies, and major guideline statements. This approach was chosen due to varied literature and scarce high-quality prospective evidence. Results: Neoadjuvant PRRT and CAPTEM-based chemotherapy demonstrate encouraging activity in selected patients with SSTR-positive or borderline resectable pNETs, though evidence is predominantly retrospective and R0 resection rates are inconsistent across modalities. Adjuvant systemic therapy lacks high-quality evidence of benefit in well-differentiated GEP-NETs whereas platinum-based chemotherapy following resection of NEC represents the only setting where adjuvant treatment is commonly recommended, albeit without randomized trial support. Liver-directed therapies, including thermal ablation, TACE, and TARE, play complementary roles in selected patients with hepatic metastases. The overall evidence base is largely retrospective and heterogenous. Management should be individualized through multidisciplinary discussion.
2026-09-15 | Lurbinectedin plus irinotecan in pretreated gastroenteropancreatic neuroendocrine neoplasms: results of a phase II expansion cohort.
A phase I/II trial (NCT02611024) evaluated the lurbinectedin 2.0 mg/m2 Day (D)1 plus irinotecan 75 mg/m2 D1 and D8 every three weeks combination in multiple solid tumors. Data from the phase II cohort of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are reported in this manuscript. Thirty-four patients with NENs (second line or greater) were included, 20 with poorly differentiated neuroendocrine carcinomas (NECs), and 14 with grade 2/3 well-differentiated neuroendocrine tumors (NETs) of digestive origin. The primary efficacy endpoint was objective response rate (ORR) according to RECIST v.1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. In patients with NECs, the ORR with lurbinectedin plus irinotecan was 15.0% [95% confidence interval (CI) 3.2%-37.9%], the median PFS was 3.1 months (95% CI 1.4-5.6 months), and the median OS was 7.2 months (95% CI 2.9-17.8 months). In patients with NETs, the ORR with lurbinectedin plus irinotecan was 7.1% (95% CI 0.2%-33.9%), the median PFS was 3.4 months (95% CI 1.4-8.9 months), and the median OS was 16.6 months (95% CI 3.9 months-not reached). The most common treatment-related adverse events were gastrointestinal disorders (nausea, 61.8% of patients; diarrhea, 44.1%; and vomiting, 35.3%), fatigue (58.8%), and decreased appetite (20.6%); these events were mostly grades 1 and 2. Grade ≥3 neutropenia was observed in 47.1% of patients and febrile neutropenia in 5.9%. Grade ≥3 transaminase increases were the most common severe laboratory biochemical abnormalities reported during treatment regardless of relationship to study drugs. The combination of lurbinectedin plus irinotecan with primary granulocyte colony-stimulating factor prophylaxis showed antitumor activity in GEP-NECs but limited activity in GEP-NETs. This combination had a predictable and manageable safety profile, with myelosuppression, gastrointestinal disorders, and fatigue as main toxicities. The lurbinectedin plus irinotecan combination deserves to be further explored in GEP-NECs after failure of platinum therapy.
2026-09-11 | Ablative magnetic resonance–guided radiation for gastrointestinal neuroendocrine tumors: assessing local control and toxicity
Background Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are an indolent subset of neuroendocrine neoplasms with a propensity to metastasize. In the case of oligoprogression, locoregional therapies are considered but may not be suitable for all patients. Stereotactic body radiotherapy, including magnetic resonance–guided radiotherapy (MRgRT), has emerged as an option to optimize local control and mitigate toxicity. Objective This study aims to evaluate the efficacy and safety of MRgRT for treating patients with GEP-NETs, focusing on local control and treatment-related toxicity. Methods A retrospective review was conducted on 25 patients diagnosed with abdominal neuroendocrine neoplasms and treated with MRgRT from 2019 to 2023. After excluding patients with neuroendocrine carcinomas and other noneligible conditions, 20 patients with well-differentiated GEP-NETs were included in the final analysis. Primary endpoints were local control and radiation toxicity; secondary endpoints were progression-free survival and overall survival calculated from the date of MRgRT. Results The study cohort had a median follow-up of 44.5 months. MRgRT was well-tolerated, with only two (10%) patients experiencing acute grade 3 treatment-related toxicity. Local control was achieved among 95% of patients, with a median progression-free survival of 30 months. No significant variables were associated with progression-free survival or toxicity in the univariate analysis. Conclusion Magnetic resonance–guided radiotherapy is a well-tolerated treatment that offers high rates of local control for patients with GEP-NETs, including those with metastatic disease. This treatment should be considered a viable alternative for patients who are not candidates for other locoregional therapies.
2026-09-11 | Comprehensive Somatic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms.
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is rising, yet their biological heterogeneity and variable response to treatments remain poorly understood. Comprehensive genomic characterization may uncover somatic drivers and inform biomarker-driven therapeutic strategies. We retrospectively analyzed clinically ordered next-generation sequencing (NGS) results from tumor samples of 111 patients with confirmed GEP-NENs treated at Johns Hopkins Hospital between 2020 and 2022. Pathogenic and likely pathogenic mutations were identified using OncoKB, CHASMplus, and COSMIC databases. Mutational patterns were correlated with clinical characteristics and overall survival using univariate and multivariate analyses. In this retrospective study of 111 patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), somatic pathogenic or likely pathogenic mutations were identified in 79% of cases. The most frequent alterations involved TP53 (19%), MEN1 (17%), and chromatin remodeling genes such as DAXX (9%) and ATRX (6%). Notably, we also identified a subset of patients (9%) patients with mutations typically associated with hematologic malignancies. Distinct co-mutation and mutual exclusivity patterns were observed between pancreatic and non-pancreatic NENs. Poorly differentiated or high-grade tumors correlated with mutations in TP53, KRAS, and CDKN2A. Mutations in KRAS, DAXX/ATRX, and hematologic malignancy-associated genes were independently associated with worse overall survival. This study reveals distinct somatic mutation patterns in GEP-NENs associated with tumor differentiation, grade, primary site, and survival. The identification of hematologic malignancy-associated mutations in a subset of GEP-NENs suggests possible shared molecular phenotypes with poor prognostic implications. The presence of KRAS mutations supports exploring pan-RAS inhibitors as potential therapies in select patients. These findings highlight the clinical utility of genomic profiling in GEP-NENs.
2026-08-26 | Proteomic landscape of pan-tissue neuroendocrine carcinomas defines subtype-specific functional architectures, biomarkers and therapeutic targets.
Neuroendocrine carcinomas (NECs) comprise a highly heterogeneous group of lethal malignancies arising from diverse anatomical sites. We aimed to provide a functional blueprint for bridging the translational gap between fundamental discovery and clinical application in NEC. Building on our previously established cross-tissue transcriptional framework, we here performed comprehensive proteomic and phosphoproteomic profiling of 267 NECs spanning 26 anatomical sites. This integrated analysis recapitulated the five ANHPY transcriptional subtypes driven by master transcription factors (ASCL1, NEUROD1, HNF4A, POU2F3 and YAP1). These subtypes hijacked distinct lineage developmental programmes, which converged with specific RB1 status to dictate their molecular identities. Synergistic profiling of tissue and plasma proteomes, alongside cell secretomes, nominated subtype-specific diagnostic and therapeutic biomarkers. Specifically, we uncovered NAD+ dependency as a metabolic vulnerability unique to subtype H, which is primarily distributed across gastroenteropancreatic NEC. Pharmacological inhibition of the NAD+ salvage enzyme NAMPT achieved complete tumour regression in vivo by triggering synthetic lethality in the context of an inherent deficiency in NAD+ biosynthesis. We also defined four tumour microenvironment (TME) subtypes that capture the extrinsic diversity of NEC. Notably, the 'inflamed' TME subtype was associated with superior immunotherapy responses, yielding an inflammatory signature that robustly stratified patients across diverse tissue origins. This study delineated conserved molecular identities, multidimensional biomarkers, the immune landscape and subtype H-specific therapeutic strategies, paving the way for precision medicine in NEC.
antibodies
2026-08-25 | Systemic therapies for gastroenteropancreatic neuroendocrine carcinomas: Current paradigm and future avenues.
Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are aggressive, poorly differentiated neoplasms representing the most common subtype of extra-pulmonary neuroendocrine carcinomas. Despite increasing recognition, they remain biologically and therapeutically elusive, with limited understanding of their molecular drivers and few established treatment paradigms. Most patients present with advanced disease, making systemic therapy the cornerstone of management. Platinum-based chemotherapy remains the standard first-line approach, though outcomes are suboptimal and consensus is lacking regarding maintenance strategies and second-line options. Later lines of therapy are ineffective, and survival is short after progression on first-line therapy. In this review, we synthesize current evidence on systemic therapies for GEP-NECs, highlighting clinical trials of cytotoxic agents, immune checkpoint inhibitors, molecularly targeted therapies, and novel modalities such as bispecific T-cell engagers. We also discuss the role of molecular profiling and emerging biomarkers in guiding therapy, with an emphasis on precision-driven approaches for this highly heterogeneous and challenging group of malignancies.
2026-08-24 | Association between PD-1/PD-L1 expression and clinicopathological parameters as well as prognosis in neuroendocrine neoplasms of the digestive system: a systematic review and meta-analysis.
Neuroendocrine neoplasms (NENs) are a highly heterogeneous group of tumors originating from the neuroendocrine system, predominantly occurring in the gastrointestinal tract and lungs. This meta-analysis aimed to clarify the association of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression with clinicopathological parameters and prognosis in patients with digestive system NENs. A systematic literature search was performed in PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Biomedical Literature Database (CBM) from each database's inception to February 2026. Eligible studies were analyzed using Stata 17.0 software, with 29 studies including 2,633 patients. Results showed no significant association between PD-1 expression and clinicopathological parameters or prognosis. In contrast, PD-L1 expression was closely correlated with high tumor grade (OR = 2.73, 95% CI: 1.33-5.60, P = 0.006) and pancreatic primary tumor site (OR = 2.58, 95% CI: 1.21-5.52, P = 0.014). Regarding prognosis, positive PD-L1 expression was associated with inferior overall survival (OS) in gastroenteropancreatic NENs (GEP-NENs) (HR = 1.77, 95% CI: 1.25-2.51, P = 0.001) but favorable OS in esophageal NENs (HR = 0.60, 95% CI: 0.37-0.99, P = 0.047). In conclusion, PD-L1 expression correlates with high tumor grade and pancreatic origin. It serves as a predictive biomarker for poor OS in GEP-NENs but favorable prognosis in esophageal NENs, highlighting the divergent prognostic value of the PD-1/PD-L1 axis across digestive system NEN subtypes. These findings provide hypothesis-generating evidence for the potential rationale of immune checkpoint inhibitors in high-grade or poorly differentiated GEP-NENs, although their clinical application requires further prospective validation.
2026-05-25 | Immunotherapeutic strategies in gastroenteropancreatic neuroendocrine neoplasms: present condition and future developments
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous malignancies frequently resistant to standard therapies. Immunotherapy represents a novel management frontier. This review synthesises clinical and translational evidence regarding immune checkpoint inhibitors (ICIs), bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cell therapies, and oncolytic virotherapy in GEP-NENs. We examine critical antigenic targets (somatostatin receptors, DLL3) and strategies to overcome the immunosuppressive tumour immune microenvironment (TIME). While single-agent ICIs show modest efficacy in well-differentiated NETs, dual checkpoint blockade exhibits durable disease control in poorly differentiated NECs. Targeted modalities like DLL3-directed bispecific antibodies demonstrate significant early efficacy. Furthermore, we summarise highly synergistic combinatorial approaches, specifically integrating immunotherapy with anti-angiogenic agents and peptide receptor radionuclide therapy (PRRT). Ongoing biomarker-driven trials and molecular profiling remain essential to optimise patient selection and treatment sequencing.
2026-05-12 | Molecular Profiling of Digestive Grade 3 Neuroendocrine Tumors Reveals a Shared Molecular Framework with Lower-Grade Tumors, Marked Heterogeneity, and Therapeutic Opportunities.
Well-differentiated neuroendocrine tumors, grade 3 (NETs G3) of the digestive system are high-grade neuroendocrine neoplasms characterized by well-differentiated neuroendocrine morphology and high proliferative activity. Their molecular identity and therapeutic vulnerabilities remain incompletely defined. We performed a transcriptomic analysis and a comprehensive genomic profiling of 40 cases, including 26 NETs G3, 8 NETs G1/G2, and 6 neuroendocrine carcinomas (NECs). Targeted sequencing assessed alterations at both the DNA and RNA level, and gene expression profiling was conducted using a targeted immune-oncology panel. NETs G3 retained recurrent alterations in chromatin-regulatory genes characteristic of well-differentiated tumors and largely lacked the consistent TP53 and RB1 inactivation typical of NECs. Transcriptomic and genomic analysis demonstrated separation of NECs from NETs, with NETs G3 partially overlapping with NETs G1/G2 supporting a model of molecular relatedness. However, when compared with NETs G1/G2, NETs G3 showed upregulation of extracellular matrix remodeling, metabolic reprogramming, and cytokine signaling pathways. NETs G3 were heterogeneous in terms of number of genomic alterations per case and involved genes. A distinctive genomic feature was the predominance of large-segment copy-number losses, frequently involving chromatin-regulatory regions on chromosomes X and 10. Potentially targetable alterations were detected in up to 25% of NETs G3. Analysis of immune microenvironment supported a poorly inflamed tumor status, with individual cases harboring microsatellite instability or enrichment in tumor-infiltrating lymphocytes potentially amenable to immunotherapy.
2026-04-13 | Real World Outcomes With Chemotherapy and Immunotherapy in Metastatic Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinomas.
Gastroenteropancreatic poorly differentiated neuroendocrine carcinomas (GEP-NECs) are aggressive cancers where cytotoxic chemotherapy is the backbone of treatment. While the addition of immunotherapy with immune checkpoint inhibitors (IOs) to chemotherapy is recommended for lung NECs, evidence regarding IO efficacy in GEP-NECs is limited. We explore outcomes with systemic therapies in patients with metastatic GEP-NECs using the National Cancer Database (NCDB). Cases of metastatic GEP-NECs with years of diagnosis between 2018 and 2022 were identified within the NCDB. Overall survival (OS) was analyzed using Kaplan-Meier estimations and Cox proportional hazards regression. Four thousand one hundred twenty-seven cases were included. 1209 (29.29%) patients did not receive any systemic therapy (chemotherapy/immunotherapy/both). Among the 2918 patients that received systemic therapy, 758 (25.98%) patients received immunotherapy (immunotherapy alone = 21; chemotherapy plus immunotherapy [chemoIO] = 737). The percentage of patients receiving immunotherapy alongside chemotherapy increased from 12.27% in 2018 to 34.18% in 2022. Two thousand two hundred eighty cases were included for survival analysis. Patients treated with chemoIO (N = 532) had prolonged OS versus chemotherapy alone (N = 1748), with median OS of 10.51 months vs. 8.31 months (HR, 0.77; 95% CI, 0.69-0.85; p < 0.001). The association was significant in all histological subgroups (small-cell, p < 0.001; large-cell, p = 0.04; others/not specified, p = 0.01). Combination chemoIO may improve survival in metastatic GEP-NECs as compared to chemotherapy alone. Results of currently ongoing clinical trials exploring the role of immunotherapy in extrapulmonary NECs may help guide clinical practice in GEP-NECs.
proteins
2026-09-24 | Next-Generation Peptide Receptor Radionuclide Therapy: A Phase 1 Dose-Escalation and Dosimetry Study of 177Lu-DOTA-EB-TATE.
Neuroendocrine tumors (NETs) are often detected late, limiting curative treatments and requiring systemic therapies such as peptide receptor radionuclide therapy (PRRT). Although 177Lu-DOTATATE has demonstrated efficacy, its rapid clearance from the circulation limits tumor radiation delivery and may increase renal toxicity risk. 177Lu-DOTA-EB-TATE, a novel PRRT agent conjugated with Evans blue for albumin binding, offers extended circulation time and enhanced tumor uptake, potentially improving therapeutic outcomes. This phase 1 study aimed to evaluate the safety, dosimetry, and preliminary efficacy of 177Lu-DOTA-EB-TATE in patients with advanced gastroenteropancreatic NETs. Methods: Six adults with inoperable, measurable gastroenteropancreatic NETs (WHO grades 2 and 3) and with somatostatin receptor overexpression were enrolled. Using a 3 + 3 dose-escalation design, patients received 177Lu-DOTA-EB-TATE at nominal activities of 1.85, 3.70, or 5.55 GBq intravenously for 2 cycles, 6 wk apart. Individualized dosimetry after the first cycle informed subsequent treatment delivery. Safety was assessed biweekly, and tumor responses were evaluated using RECIST at 3 and 6 mo. Results: Treatment was well-tolerated, with mild side effects, including nausea, fatigue, and hair loss; no renal toxicity occurred. The median kidney absorbed dose per cycle was 4.8 Gy (range, 2.9-8.9 Gy; mean, 2.2 Gy/GBq). Hematologic toxicity was dose-limiting, with persistent grade 3 febrile neutropenia observed at 3.7 GBq in 1 patient and confirmed in an external cohort. Thus, the maximum tolerated activity was set at 3.70 GBq and the recommended phase 2 activity at 1.85 GBq per cycle to avoid irreversible marrow suppression. Tumor responses included stable disease (n = 5) and partial response (n = 1) at 3 mo; disease progressed in 2 patients at 6 mo after treatment completion. Conclusion: The 2-cycle regimen of 177Lu-DOTA-EB-TATE delivered higher renal absorbed doses compared with standard 177Lu-DOTATATE. With individualized dosimetry, no kidney toxicity was observed. However, increased retention in the circulation caused hematologic-related side effects and made marrow the dose-limiting organ. Within the defined dosing limits of this study, 177Lu-DOTA-EB-TATE is a potential high-uptake alternative to standard PRRT, supporting a shortened 2-cycle schedule for earlier response assessment. Further research should refine dosing schedules and patient selection to balance efficacy and safety.
2026-09-24 | Optimizing the Therapeutic Index: Sequential Intraarterial-Intravenous PRRT with Personalized Volumetric-Adjusted Dosing.
Patients with well-differentiated neuroendocrine tumors (NETs) frequently present with liver-dominant metastases, which significantly impact prognosis and limit curative options. Although standard intravenous peptide receptor radionuclide therapy with 177Lu-DOTATATE is effective, strategies to intensify the radiation dose to hepatic lesions are needed to improve outcomes. This prospective clinical trial investigated the feasibility, tolerability, and preliminary efficacy of a personalized treatment schedule combining intraarterial and intravenous administrations of 177Lu-DOTATATE. Methods: Ten consecutive adults with progressive, nonresectable, liver-dominant metastatic gastroenteropancreatic NETs expressing somatostatin receptors were enrolled. The treatment protocol comprised 4 cycles of 177Lu-DOTATATE administered every 2 mo (2 initial intraarterial cycles followed by 2 intravenous cycles). Intraarterial administration involved angiographically guided, selective catheterization of the hepatic arteries with volumetrically adjusted activity to maximize targeted delivery. Safety monitoring, radiation protection, and dosimetry comparisons between intraarterial and intravenous routes were performed. Results: The intraarterial administration procedure was feasible in 100% of patients. Radiation exposure to staff and patients remained within regulatory limits, with no contamination events. Dosimetry analysis indicated that intraarterial administration (cycle 1) delivered a greater than 3-fold higher radiation dose to liver metastases compared with the intravenous route (cycle 3), although interim response may have played a role. Furthermore, 68Ga-DOTATATE PET imaging revealed an 86% increase in median liver lesion uptake with intraarterial administration. The regimen was generally well-tolerated, with only 1 severe adverse event reported (low esophageal tear), which was not attributed to the administration route. Efficacy analysis showed partial response rates in 67% of patients at the first follow-up 3 mo after treatment completion, improving to 87% at the second follow-up (6 mo) in accordance with RECIST and volumetric criteria. Conclusion: The sequential administration of intraarterial followed by intravenous 177Lu-DOTATATE is a feasible and safe therapeutic strategy for liver-dominant metastatic NETs. The use of a personalized, volumetric-based approach provided higher uptake and absorbed doses in hepatic metastases, with high objective response rates and effectively maintained systemic coverage.
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.
2026-08-02 | Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been in use for 20 years. There have been concerns about their safety in patients with neuroendocrine neoplasms (NENs). The reports of GLP-1 receptor (GLP-1R)-driven proliferation of C-cell neoplasms in rodent studies had led to the black-box warning against their use in patients with medullary thyroid carcinoma or multiple endocrine neoplasia type 2. In this review, we have attempted to evaluate the physiological and pathological expression of GLP-1Rs in various endocrine organs and summarize the preclinical and clinical evidence regarding the effect of GLP-1RA exposure and risk of NENs. Glucagon-like peptide-1 receptor expression has not only been found in non-neoplastic tissues such as neurohypophysis, duodenal glands and pancreatic islets, but also in neuroendocrine tumors (NETs). Preclinical studies have demonstrated the proliferative effects of GLP-1RA in cell lines representing pancreatic NETs and small intestinal NETs. The available data from retrospective studies, randomized trials and cancer registries provide conflicting data and do not support a generalized increase in NENs with the use of GLP-1RA. Some epidemiological studies have even shown survival benefits associated with GLP-1RA use. In addition, significant gaps in evidence remain, such as lack of data regarding certain tumor subtypes, long-term prospective studies with NENs as the clinical endpoint and uncertainty regarding patients with multiple endocrine neoplasia type 1. Hence, the initiation of GLP-1RA therapy in patient with predisposition to NENs where a contraindication does not exist, should be approached cautiously with careful monitoring for long-term adverse effects.
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.
cell therapies
2026-09-30 | Controversies in NEN: An ENETS position statement on the role of liver transplantation (LT) in patients with advanced small-intestinal and pancreatic NETs.
Liver transplantation (LT) may offer survival or symptomatic benefit for highly selected patients with advanced, well-differentiated small-intestinal or pancreatic neuroendocrine tumours and unresectable liver-dominant metastases. However, its role remains controversial, as LT is rarely curative, recurrence is common, and benefits must be weighed against perioperative risk, lifelong immunosuppression, alternative therapies, and organ allocation ethics. This ENETS position statement summarises current evidence and expert consensus, reframing LT within a transplant-benefit model rather than fixed eligibility criteria. It outlines biologically informed selection principles and multidisciplinary assessment, as well as addressing the need for standardised characterisation, prospective registries, and long-term outcome data to better define the net clinical benefit of LT in this rare patient population.
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.
2026-03-09 | [Research progress on liver transplantation therapy for hepatic metastases in gastroenteropancreatic neuroendocrine tumors].
Neuroendocrine tumors are rare, low-grade malignant tumors with a gradually increasing incidence rate in recent years, with gastroenteropancreatic neuroendocrine tumors being the most common among them. The majority of gastropancreatic neuroendocrine tumors have already metastasized to the liver at the time of initial diagnosis; therefore, treatment targeting liver metastases is crucial. The most effective treatment for hepatic metastases of gastropancreatic neuroendocrine tumors is surgical resection. However, 60%-70% of patients are ineligible for radical resection due to diffuse liver involvement. Thus, an alternative treatment option offered for these patients is liver transplantation. Liver transplantation is considered an indication for well-differentiated, unresectable hepatic metastases of gastropancreatic neuroendocrine tumors because of the tumor's low invasiveness, slow growth, and the fact that the liver is often the only distant metastasis site. This article reviews the research progress of liver transplantation therapy for hepatic metastases in gastropancreatic neuroendocrine tumors.
2026-01-10 | Personalized Drug Screening and Risk Assessment in Patient-Derived Gastroenteropancreatic Neuroendocrine Neoplasms.
Precision medicine has transformed many areas in oncology. However, it remains largely unexplored in metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), where there is a need for further innovative therapies. To evaluate individual tumor responses to different agents, we have established a standardized personalized drug screening and risk assessment platform using patient-derived GEP-NEN primary cultures (n = 23, 16/23 from metastatic tumors, n = 12 small intestinal neuroendocrine tumors [siNETs], n = 10 pancreatic NETs [pNETs], n = 1 neuroendocrine carcinoma [NEC]). We assessed GEP-NEN primary culture cell viability, performed signaling pathway analysis by automated Western blotting and immunohistochemically evaluated tumor composition. Systematic drug testing of 27 agents including signaling inhibitors (i) (mechanistic target of rapamycin inhibitor [mTORi] everolimus, tyrosine kinase inhibitors cabozantinib/sunitinib, AKTi capivasertib, PI3Ki alpelisib, CDK4/6i ribociclib), DNA damage response inhibitors (PARPi niraparib, WEE1i adavosertib, ATRi berzosertib), chemotherapeutics (temozolomide, 5-fluorouracil, lurbinectedin), drug repurposed agents (zoledronic acid), and a personalized risk assessment (glucagon-like peptide [GLP]-2 analogue teduglutide, GLP-1 analogue semaglutide, sex hormones) was performed. We demonstrated statistically significant group effects and individualized responsiveness/resistance data. We identified differences in drug response between pNETs/siNETs and between GEP-NETs/GEP-NEC, respectively. We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.
2025-04-11 | Safety of loco-regional treatments in neuroendocrine liver metastases compared to an hepato-cellular carcinoma cohort: a single-center study.
Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) present with neuroendocrine liver metastases (NELM) in approximately 60% of the cases. Loco-regional interventional radiology procedures are widely used in the treatment of hepatocellular carcinoma (HCC) and have been increasingly used in recent years also in the setting of NELM. We aimed to assess the safety and, as a secondary aim, the local response of trans-arterial embolization (TAE) in NELM in our consecutive cohort of GEP-NEN patients. We collected data from all consecutive patients who underwent TAE for NELM secondary to GEP-NENs at IRCCS Humanitas Research Hospital, from March 2014 to February 2024. Safety and efficacy data were retrospectively collected. Short-term procedure-related adverse events (AE) were classified according to the new Society of Interventional Radiology classification. An internal analysis was also carried out on results from a cohort of patients with compensated advanced chronic liver disease complicated by HCC and treated with TAE. A total of 45 procedures in 21 patients were consecutively performed during the study period. Mean age at diagnosis was 56.6 years (SD 12.6) and median follow-up time was 60 months (range 10-169). At the time of treatment, the disease was bilobar in 19 cases (90.4%), with multifocal metastases present in 11 cases (52.3%). Adverse events were defined immediate (within 24 h from the procedure), early (within 30 days after the procedure), and late (> 30 days after the procedure). The rate of complications was 33.3% (N = 15), mostly comprising sepsis (73.3%, N = 11) which in 2 patients was secondary to the development of a perilesional abscess, requiring extended antibiotic therapy and, in one case, percutaneous drainage. Only one case of post-procedural bleeding was reported, which required further radiological embolization. Other less common AEs were reported, including acute post-procedural hepatitis, acute heart failure, and a generalized urticarial skin rash. The median length of hospitalization per procedure was 3 days (range 1-49). Only one tumor-related death was reported during the follow-up period. Disease stabilization or partial response was achieved in 86.6% (N = 39) of the procedures. In the HCC population a lower complication rate was observed: 6.10%, 5/82 patients: 3 were represented by liver abscess, one by acute-on-chronic liver failure and one by hepatic ischemia and consequent liver decompensation with ascites. 33 patients developed partial response (33/82, 40.24%). At one-year follow-up a 82.93% recurrence rate and a 1.22% mortality rate were detected. While loco-regional radiological treatments are recognized as safe and effective treatments for HCC, in the setting of NELM few data are available. In the current series TAE could represent a promising option for NELM treatment. The complication rate in NELM setting appears slightly higher than that reported both in the literature and in our own series for HCC treatment. Further studies are needed to fully assess TAE safety in NELM setting.
other
2026-07-04 | Epigenetic Dysregulation of Somatostatin Receptors (SSTR) 1-5 and Therapeutic Implications in Neuroendocrine and Non-Neuroendocrine Malignancies.
Somatostatin receptors (SSTR) mediate the antiproliferative, antisecretory, and proapoptotic effects of somatostatin and its synthetic analogs. Their surface expression on neuroendocrine tumor (NET) cells is required for somatostatin analog therapy and radiopharmaceutical therapy (RPT). However, 20%-30% of gastroenteropancreatic NETs and most poorly differentiated neuroendocrine carcinomas show insufficient SSTR expression, limiting therapeutic eligibility. Accumulating evidence indicates that reversible epigenetic mechanisms contribute substantially to SSTR loss, alongside tumor dedifferentiation, lineage-state changes, and clonal evolution with DNA hypermethylation of the SSTR2 promoter representing a central event, complemented by chromatin remodeling and non-coding RNA-mediated regulation. Preclinical studies demonstrate that epigenetic therapies, including DNA methyltransferase and histone deacetylase inhibitors, can restore functional SSTR expression. Notably, the first-in-human LANTana trial provides clinical proof-of-concept that epigenetic priming with oral decitabine/cedazuridine can induce SSTR2 re-expression and enable subsequent RPT in receptor-negative tumors. This review synthesizes current knowledge of epigenetic regulation across all five SSTR subtypes (SSTR1-SSTR5), examines receptor silencing in neuroendocrine and non-neuroendocrine malignancies, and critically evaluates the preclinical and clinical evidence supporting therapeutic strategies that target these mechanisms.
2025-11-14 | Data from Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A Multicohort, Basket, Phase II Trial (CABATEN/GETNE-T1914)
<div>AbstractPurpose:<p>Multikinase inhibitors have shown efficacy in endocrine neoplasms, and synergism with immune checkpoint inhibitors has been noted in other tumors.</p>Patients and Methods:<p>This is a prospective, multicenter, open-label, Simon two-stage optimal design, phase II study including patients with advanced and refractory endocrine and neuroendocrine neoplasms in six cohorts: lung well-differentiated neuroendocrine tumors, anaplastic thyroid cancer (ATC), adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET), and grade 3 extrapulmonary neuroendocrine neoplasms. Patients received atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 40 mg/day orally until disease progression or unacceptable toxicity. The primary objective was the overall response rate (ORR) by RECIST 1.1.</p>Results:<p>From October 2020 to December 2022, 93 patients were included. The ORR was 14.3% [95% confidence interval (CI), 1.8–42.8] in ATC (<i>N</i> = 14); 8.3% (95% CI, 1.0–27.0) in ACC (<i>N</i> = 24); 15.4% (95% CI, 1.9–45.5) in PPGL (<i>N</i> = 13), and 16.7% (95% CI, 4.7–37.4) in GEP-NET (<i>N</i> = 24). Lung well-differentiated neuroendocrine tumors and grade 3 extrapulmonary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in PPGL, and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6% and 47.6%, respectively. No unexpected toxicity was observed.</p>Conclusions:<p>Cabozantinib and atezolizumab were safely administered and showed promising ORR, and preliminary long-term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.</p></div>
2025-05-20 | Impact of multikinase inhibitors in reshaping the treatment of advanced gastroenteropancreatic neuroendocrine tumors.
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.
2025-04-18 | Investigation of an oncolytic herpes simplex virus as a potential therapeutic agent for gastroenteropancreatic neuroendocrine neoplasms.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) present unique challenges due to their heterogeneity and limited treatment options. Oncolytic virotherapy has emerged as a promising therapeutic for other NETs and thus, we sought to investigate the potential of an engineered oncolytic herpes simplex virus (oHSV), M002, for GEP-NETS. We employed an established long-term passage GEP-NET cell line and a unique, human pediatric patient-derived xenograft GEP-NET line. We found the virus to effectively infect, replicate within, and kill both cell lines in vitro. Similar effects were noted in vivo, with M002 decreasing tumor growth and improving overall survival in mice bearing tumors from both the established cell line and human GEP-NET PDX. Overall, these studies provide an evaluation of an oncolytic HSV in GEP-NETs, highlighting its therapeutic potential and considerations for clinical translation.
2025-04-10 | Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors with limited treatment options. This phase 2 Bayesian study evaluated the combination of regorafenib, a multikinase inhibitor, and avelumab, a programmed death 1 (PD1) ligand 1 inhibitor, in advanced grade 2-grade 3 well-differentiated GEP neuroendocrine tumors or grade 3 GEP neuroendocrine carcinomas after progression on prior therapies. A total of 47 participants were enrolled and 42 were evaluable for efficacy. Participants received regorafenib (160 mg per day) and avelumab (10 mg kg-1 biweekly) in 28-day cycles. The primary endpoint, 6-month objective response rate per the response evaluation criteria in solid tumors version 1.1, was 18% (95% confidence interval (CI): 8-31%), with a median progression-free survival of 5.5 months (95% CI: 3.6-8). Durable responses were noted (16.6 months; 95% CI: 3.7-no response). Treatment-related adverse events were manageable, with fatigue, diarrhea and palmar-plantar erythrodysesthesia being most common. Exploratory biomarker analysis identified PD1 and indoleamine 2,3-dioxygenase 1 expression and activity as potential resistance markers. These findings highlight the clinical potential of regorafenib and avelumab in GEP-NENs, emphasizing the need for predictive biomarkers and validation in future randomized trials. Clinical Trial registration: NCT03475953 .
small molecules
2026-09-26 | The Use of Adjunct Therapies with Surgery for Gastroenteropancreatic Neuroendocrine Tumors: Indications, Timing, and Outcomes.
Background/Objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare biologically heterogeneous neoplasms but with increasing incidence in recent years. Surgery remains the backbone of treatment; however, long-term recurrence is common even after curative resection. Despite expanding treatment options, the optimal perioperative integration of adjunct therapies in conjunction with surgery remains incompletely defined, as available evidence is largely retrospective and heterogeneous. This review critically synthesizes available evidence on the role of perioperative therapies in the surgical management of GEP-NENs, identifies key knowledge gaps, and highlights areas where multidisciplinary decision-making is required. Methods: A targeted narrative literature review was performed in PubMed/MEDLINE (2001-2026), supplemented by ClinicalTrials.gov and major society guidelines. Predefined search terms were used to include "gastroenteropancreatic neuroendocrine tumor", "GEP-NET", "pancreatic neuroendocrine tumor", "surgery", "palliative surgery", "neoadjuvant", "adjuvant", "PRRT", "somatostatin analogue", "chemotherapy", "targeted therapy", "immune checkpoint inhibitor", and "liver-directed therapy". Studies were selected based on relevance, with emphasis on comprehensive reviews, key clinical studies, and major guideline statements. This approach was chosen due to varied literature and scarce high-quality prospective evidence. Results: Neoadjuvant PRRT and CAPTEM-based chemotherapy demonstrate encouraging activity in selected patients with SSTR-positive or borderline resectable pNETs, though evidence is predominantly retrospective and R0 resection rates are inconsistent across modalities. Adjuvant systemic therapy lacks high-quality evidence of benefit in well-differentiated GEP-NETs whereas platinum-based chemotherapy following resection of NEC represents the only setting where adjuvant treatment is commonly recommended, albeit without randomized trial support. Liver-directed therapies, including thermal ablation, TACE, and TARE, play complementary roles in selected patients with hepatic metastases. The overall evidence base is largely retrospective and heterogenous. Management should be individualized through multidisciplinary discussion.
2026-09-15 | Lurbinectedin plus irinotecan in pretreated gastroenteropancreatic neuroendocrine neoplasms: results of a phase II expansion cohort.
A phase I/II trial (NCT02611024) evaluated the lurbinectedin 2.0 mg/m2 Day (D)1 plus irinotecan 75 mg/m2 D1 and D8 every three weeks combination in multiple solid tumors. Data from the phase II cohort of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are reported in this manuscript. Thirty-four patients with NENs (second line or greater) were included, 20 with poorly differentiated neuroendocrine carcinomas (NECs), and 14 with grade 2/3 well-differentiated neuroendocrine tumors (NETs) of digestive origin. The primary efficacy endpoint was objective response rate (ORR) according to RECIST v.1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. In patients with NECs, the ORR with lurbinectedin plus irinotecan was 15.0% [95% confidence interval (CI) 3.2%-37.9%], the median PFS was 3.1 months (95% CI 1.4-5.6 months), and the median OS was 7.2 months (95% CI 2.9-17.8 months). In patients with NETs, the ORR with lurbinectedin plus irinotecan was 7.1% (95% CI 0.2%-33.9%), the median PFS was 3.4 months (95% CI 1.4-8.9 months), and the median OS was 16.6 months (95% CI 3.9 months-not reached). The most common treatment-related adverse events were gastrointestinal disorders (nausea, 61.8% of patients; diarrhea, 44.1%; and vomiting, 35.3%), fatigue (58.8%), and decreased appetite (20.6%); these events were mostly grades 1 and 2. Grade ≥3 neutropenia was observed in 47.1% of patients and febrile neutropenia in 5.9%. Grade ≥3 transaminase increases were the most common severe laboratory biochemical abnormalities reported during treatment regardless of relationship to study drugs. The combination of lurbinectedin plus irinotecan with primary granulocyte colony-stimulating factor prophylaxis showed antitumor activity in GEP-NECs but limited activity in GEP-NETs. This combination had a predictable and manageable safety profile, with myelosuppression, gastrointestinal disorders, and fatigue as main toxicities. The lurbinectedin plus irinotecan combination deserves to be further explored in GEP-NECs after failure of platinum therapy.
2026-09-11 | Ablative magnetic resonance–guided radiation for gastrointestinal neuroendocrine tumors: assessing local control and toxicity
Background Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are an indolent subset of neuroendocrine neoplasms with a propensity to metastasize. In the case of oligoprogression, locoregional therapies are considered but may not be suitable for all patients. Stereotactic body radiotherapy, including magnetic resonance–guided radiotherapy (MRgRT), has emerged as an option to optimize local control and mitigate toxicity. Objective This study aims to evaluate the efficacy and safety of MRgRT for treating patients with GEP-NETs, focusing on local control and treatment-related toxicity. Methods A retrospective review was conducted on 25 patients diagnosed with abdominal neuroendocrine neoplasms and treated with MRgRT from 2019 to 2023. After excluding patients with neuroendocrine carcinomas and other noneligible conditions, 20 patients with well-differentiated GEP-NETs were included in the final analysis. Primary endpoints were local control and radiation toxicity; secondary endpoints were progression-free survival and overall survival calculated from the date of MRgRT. Results The study cohort had a median follow-up of 44.5 months. MRgRT was well-tolerated, with only two (10%) patients experiencing acute grade 3 treatment-related toxicity. Local control was achieved among 95% of patients, with a median progression-free survival of 30 months. No significant variables were associated with progression-free survival or toxicity in the univariate analysis. Conclusion Magnetic resonance–guided radiotherapy is a well-tolerated treatment that offers high rates of local control for patients with GEP-NETs, including those with metastatic disease. This treatment should be considered a viable alternative for patients who are not candidates for other locoregional therapies.
2026-09-11 | Comprehensive Somatic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms.
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is rising, yet their biological heterogeneity and variable response to treatments remain poorly understood. Comprehensive genomic characterization may uncover somatic drivers and inform biomarker-driven therapeutic strategies. We retrospectively analyzed clinically ordered next-generation sequencing (NGS) results from tumor samples of 111 patients with confirmed GEP-NENs treated at Johns Hopkins Hospital between 2020 and 2022. Pathogenic and likely pathogenic mutations were identified using OncoKB, CHASMplus, and COSMIC databases. Mutational patterns were correlated with clinical characteristics and overall survival using univariate and multivariate analyses. In this retrospective study of 111 patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), somatic pathogenic or likely pathogenic mutations were identified in 79% of cases. The most frequent alterations involved TP53 (19%), MEN1 (17%), and chromatin remodeling genes such as DAXX (9%) and ATRX (6%). Notably, we also identified a subset of patients (9%) patients with mutations typically associated with hematologic malignancies. Distinct co-mutation and mutual exclusivity patterns were observed between pancreatic and non-pancreatic NENs. Poorly differentiated or high-grade tumors correlated with mutations in TP53, KRAS, and CDKN2A. Mutations in KRAS, DAXX/ATRX, and hematologic malignancy-associated genes were independently associated with worse overall survival. This study reveals distinct somatic mutation patterns in GEP-NENs associated with tumor differentiation, grade, primary site, and survival. The identification of hematologic malignancy-associated mutations in a subset of GEP-NENs suggests possible shared molecular phenotypes with poor prognostic implications. The presence of KRAS mutations supports exploring pan-RAS inhibitors as potential therapies in select patients. These findings highlight the clinical utility of genomic profiling in GEP-NENs.
2026-08-26 | Proteomic landscape of pan-tissue neuroendocrine carcinomas defines subtype-specific functional architectures, biomarkers and therapeutic targets.
Neuroendocrine carcinomas (NECs) comprise a highly heterogeneous group of lethal malignancies arising from diverse anatomical sites. We aimed to provide a functional blueprint for bridging the translational gap between fundamental discovery and clinical application in NEC. Building on our previously established cross-tissue transcriptional framework, we here performed comprehensive proteomic and phosphoproteomic profiling of 267 NECs spanning 26 anatomical sites. This integrated analysis recapitulated the five ANHPY transcriptional subtypes driven by master transcription factors (ASCL1, NEUROD1, HNF4A, POU2F3 and YAP1). These subtypes hijacked distinct lineage developmental programmes, which converged with specific RB1 status to dictate their molecular identities. Synergistic profiling of tissue and plasma proteomes, alongside cell secretomes, nominated subtype-specific diagnostic and therapeutic biomarkers. Specifically, we uncovered NAD+ dependency as a metabolic vulnerability unique to subtype H, which is primarily distributed across gastroenteropancreatic NEC. Pharmacological inhibition of the NAD+ salvage enzyme NAMPT achieved complete tumour regression in vivo by triggering synthetic lethality in the context of an inherent deficiency in NAD+ biosynthesis. We also defined four tumour microenvironment (TME) subtypes that capture the extrinsic diversity of NEC. Notably, the 'inflamed' TME subtype was associated with superior immunotherapy responses, yielding an inflammatory signature that robustly stratified patients across diverse tissue origins. This study delineated conserved molecular identities, multidimensional biomarkers, the immune landscape and subtype H-specific therapeutic strategies, paving the way for precision medicine in NEC.
antibodies
2026-08-25 | Systemic therapies for gastroenteropancreatic neuroendocrine carcinomas: Current paradigm and future avenues.
Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are aggressive, poorly differentiated neoplasms representing the most common subtype of extra-pulmonary neuroendocrine carcinomas. Despite increasing recognition, they remain biologically and therapeutically elusive, with limited understanding of their molecular drivers and few established treatment paradigms. Most patients present with advanced disease, making systemic therapy the cornerstone of management. Platinum-based chemotherapy remains the standard first-line approach, though outcomes are suboptimal and consensus is lacking regarding maintenance strategies and second-line options. Later lines of therapy are ineffective, and survival is short after progression on first-line therapy. In this review, we synthesize current evidence on systemic therapies for GEP-NECs, highlighting clinical trials of cytotoxic agents, immune checkpoint inhibitors, molecularly targeted therapies, and novel modalities such as bispecific T-cell engagers. We also discuss the role of molecular profiling and emerging biomarkers in guiding therapy, with an emphasis on precision-driven approaches for this highly heterogeneous and challenging group of malignancies.
2026-08-24 | Association between PD-1/PD-L1 expression and clinicopathological parameters as well as prognosis in neuroendocrine neoplasms of the digestive system: a systematic review and meta-analysis.
Neuroendocrine neoplasms (NENs) are a highly heterogeneous group of tumors originating from the neuroendocrine system, predominantly occurring in the gastrointestinal tract and lungs. This meta-analysis aimed to clarify the association of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression with clinicopathological parameters and prognosis in patients with digestive system NENs. A systematic literature search was performed in PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Biomedical Literature Database (CBM) from each database's inception to February 2026. Eligible studies were analyzed using Stata 17.0 software, with 29 studies including 2,633 patients. Results showed no significant association between PD-1 expression and clinicopathological parameters or prognosis. In contrast, PD-L1 expression was closely correlated with high tumor grade (OR = 2.73, 95% CI: 1.33-5.60, P = 0.006) and pancreatic primary tumor site (OR = 2.58, 95% CI: 1.21-5.52, P = 0.014). Regarding prognosis, positive PD-L1 expression was associated with inferior overall survival (OS) in gastroenteropancreatic NENs (GEP-NENs) (HR = 1.77, 95% CI: 1.25-2.51, P = 0.001) but favorable OS in esophageal NENs (HR = 0.60, 95% CI: 0.37-0.99, P = 0.047). In conclusion, PD-L1 expression correlates with high tumor grade and pancreatic origin. It serves as a predictive biomarker for poor OS in GEP-NENs but favorable prognosis in esophageal NENs, highlighting the divergent prognostic value of the PD-1/PD-L1 axis across digestive system NEN subtypes. These findings provide hypothesis-generating evidence for the potential rationale of immune checkpoint inhibitors in high-grade or poorly differentiated GEP-NENs, although their clinical application requires further prospective validation.
2026-05-25 | Immunotherapeutic strategies in gastroenteropancreatic neuroendocrine neoplasms: present condition and future developments
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous malignancies frequently resistant to standard therapies. Immunotherapy represents a novel management frontier. This review synthesises clinical and translational evidence regarding immune checkpoint inhibitors (ICIs), bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cell therapies, and oncolytic virotherapy in GEP-NENs. We examine critical antigenic targets (somatostatin receptors, DLL3) and strategies to overcome the immunosuppressive tumour immune microenvironment (TIME). While single-agent ICIs show modest efficacy in well-differentiated NETs, dual checkpoint blockade exhibits durable disease control in poorly differentiated NECs. Targeted modalities like DLL3-directed bispecific antibodies demonstrate significant early efficacy. Furthermore, we summarise highly synergistic combinatorial approaches, specifically integrating immunotherapy with anti-angiogenic agents and peptide receptor radionuclide therapy (PRRT). Ongoing biomarker-driven trials and molecular profiling remain essential to optimise patient selection and treatment sequencing.
2026-05-12 | Molecular Profiling of Digestive Grade 3 Neuroendocrine Tumors Reveals a Shared Molecular Framework with Lower-Grade Tumors, Marked Heterogeneity, and Therapeutic Opportunities.
Well-differentiated neuroendocrine tumors, grade 3 (NETs G3) of the digestive system are high-grade neuroendocrine neoplasms characterized by well-differentiated neuroendocrine morphology and high proliferative activity. Their molecular identity and therapeutic vulnerabilities remain incompletely defined. We performed a transcriptomic analysis and a comprehensive genomic profiling of 40 cases, including 26 NETs G3, 8 NETs G1/G2, and 6 neuroendocrine carcinomas (NECs). Targeted sequencing assessed alterations at both the DNA and RNA level, and gene expression profiling was conducted using a targeted immune-oncology panel. NETs G3 retained recurrent alterations in chromatin-regulatory genes characteristic of well-differentiated tumors and largely lacked the consistent TP53 and RB1 inactivation typical of NECs. Transcriptomic and genomic analysis demonstrated separation of NECs from NETs, with NETs G3 partially overlapping with NETs G1/G2 supporting a model of molecular relatedness. However, when compared with NETs G1/G2, NETs G3 showed upregulation of extracellular matrix remodeling, metabolic reprogramming, and cytokine signaling pathways. NETs G3 were heterogeneous in terms of number of genomic alterations per case and involved genes. A distinctive genomic feature was the predominance of large-segment copy-number losses, frequently involving chromatin-regulatory regions on chromosomes X and 10. Potentially targetable alterations were detected in up to 25% of NETs G3. Analysis of immune microenvironment supported a poorly inflamed tumor status, with individual cases harboring microsatellite instability or enrichment in tumor-infiltrating lymphocytes potentially amenable to immunotherapy.
2026-04-13 | Real World Outcomes With Chemotherapy and Immunotherapy in Metastatic Poorly Differentiated Gastroenteropancreatic Neuroendocrine Carcinomas.
Gastroenteropancreatic poorly differentiated neuroendocrine carcinomas (GEP-NECs) are aggressive cancers where cytotoxic chemotherapy is the backbone of treatment. While the addition of immunotherapy with immune checkpoint inhibitors (IOs) to chemotherapy is recommended for lung NECs, evidence regarding IO efficacy in GEP-NECs is limited. We explore outcomes with systemic therapies in patients with metastatic GEP-NECs using the National Cancer Database (NCDB). Cases of metastatic GEP-NECs with years of diagnosis between 2018 and 2022 were identified within the NCDB. Overall survival (OS) was analyzed using Kaplan-Meier estimations and Cox proportional hazards regression. Four thousand one hundred twenty-seven cases were included. 1209 (29.29%) patients did not receive any systemic therapy (chemotherapy/immunotherapy/both). Among the 2918 patients that received systemic therapy, 758 (25.98%) patients received immunotherapy (immunotherapy alone = 21; chemotherapy plus immunotherapy [chemoIO] = 737). The percentage of patients receiving immunotherapy alongside chemotherapy increased from 12.27% in 2018 to 34.18% in 2022. Two thousand two hundred eighty cases were included for survival analysis. Patients treated with chemoIO (N = 532) had prolonged OS versus chemotherapy alone (N = 1748), with median OS of 10.51 months vs. 8.31 months (HR, 0.77; 95% CI, 0.69-0.85; p < 0.001). The association was significant in all histological subgroups (small-cell, p < 0.001; large-cell, p = 0.04; others/not specified, p = 0.01). Combination chemoIO may improve survival in metastatic GEP-NECs as compared to chemotherapy alone. Results of currently ongoing clinical trials exploring the role of immunotherapy in extrapulmonary NECs may help guide clinical practice in GEP-NECs.
proteins
2026-09-24 | Next-Generation Peptide Receptor Radionuclide Therapy: A Phase 1 Dose-Escalation and Dosimetry Study of 177Lu-DOTA-EB-TATE.
Neuroendocrine tumors (NETs) are often detected late, limiting curative treatments and requiring systemic therapies such as peptide receptor radionuclide therapy (PRRT). Although 177Lu-DOTATATE has demonstrated efficacy, its rapid clearance from the circulation limits tumor radiation delivery and may increase renal toxicity risk. 177Lu-DOTA-EB-TATE, a novel PRRT agent conjugated with Evans blue for albumin binding, offers extended circulation time and enhanced tumor uptake, potentially improving therapeutic outcomes. This phase 1 study aimed to evaluate the safety, dosimetry, and preliminary efficacy of 177Lu-DOTA-EB-TATE in patients with advanced gastroenteropancreatic NETs. Methods: Six adults with inoperable, measurable gastroenteropancreatic NETs (WHO grades 2 and 3) and with somatostatin receptor overexpression were enrolled. Using a 3 + 3 dose-escalation design, patients received 177Lu-DOTA-EB-TATE at nominal activities of 1.85, 3.70, or 5.55 GBq intravenously for 2 cycles, 6 wk apart. Individualized dosimetry after the first cycle informed subsequent treatment delivery. Safety was assessed biweekly, and tumor responses were evaluated using RECIST at 3 and 6 mo. Results: Treatment was well-tolerated, with mild side effects, including nausea, fatigue, and hair loss; no renal toxicity occurred. The median kidney absorbed dose per cycle was 4.8 Gy (range, 2.9-8.9 Gy; mean, 2.2 Gy/GBq). Hematologic toxicity was dose-limiting, with persistent grade 3 febrile neutropenia observed at 3.7 GBq in 1 patient and confirmed in an external cohort. Thus, the maximum tolerated activity was set at 3.70 GBq and the recommended phase 2 activity at 1.85 GBq per cycle to avoid irreversible marrow suppression. Tumor responses included stable disease (n = 5) and partial response (n = 1) at 3 mo; disease progressed in 2 patients at 6 mo after treatment completion. Conclusion: The 2-cycle regimen of 177Lu-DOTA-EB-TATE delivered higher renal absorbed doses compared with standard 177Lu-DOTATATE. With individualized dosimetry, no kidney toxicity was observed. However, increased retention in the circulation caused hematologic-related side effects and made marrow the dose-limiting organ. Within the defined dosing limits of this study, 177Lu-DOTA-EB-TATE is a potential high-uptake alternative to standard PRRT, supporting a shortened 2-cycle schedule for earlier response assessment. Further research should refine dosing schedules and patient selection to balance efficacy and safety.
2026-09-24 | Optimizing the Therapeutic Index: Sequential Intraarterial-Intravenous PRRT with Personalized Volumetric-Adjusted Dosing.
Patients with well-differentiated neuroendocrine tumors (NETs) frequently present with liver-dominant metastases, which significantly impact prognosis and limit curative options. Although standard intravenous peptide receptor radionuclide therapy with 177Lu-DOTATATE is effective, strategies to intensify the radiation dose to hepatic lesions are needed to improve outcomes. This prospective clinical trial investigated the feasibility, tolerability, and preliminary efficacy of a personalized treatment schedule combining intraarterial and intravenous administrations of 177Lu-DOTATATE. Methods: Ten consecutive adults with progressive, nonresectable, liver-dominant metastatic gastroenteropancreatic NETs expressing somatostatin receptors were enrolled. The treatment protocol comprised 4 cycles of 177Lu-DOTATATE administered every 2 mo (2 initial intraarterial cycles followed by 2 intravenous cycles). Intraarterial administration involved angiographically guided, selective catheterization of the hepatic arteries with volumetrically adjusted activity to maximize targeted delivery. Safety monitoring, radiation protection, and dosimetry comparisons between intraarterial and intravenous routes were performed. Results: The intraarterial administration procedure was feasible in 100% of patients. Radiation exposure to staff and patients remained within regulatory limits, with no contamination events. Dosimetry analysis indicated that intraarterial administration (cycle 1) delivered a greater than 3-fold higher radiation dose to liver metastases compared with the intravenous route (cycle 3), although interim response may have played a role. Furthermore, 68Ga-DOTATATE PET imaging revealed an 86% increase in median liver lesion uptake with intraarterial administration. The regimen was generally well-tolerated, with only 1 severe adverse event reported (low esophageal tear), which was not attributed to the administration route. Efficacy analysis showed partial response rates in 67% of patients at the first follow-up 3 mo after treatment completion, improving to 87% at the second follow-up (6 mo) in accordance with RECIST and volumetric criteria. Conclusion: The sequential administration of intraarterial followed by intravenous 177Lu-DOTATATE is a feasible and safe therapeutic strategy for liver-dominant metastatic NETs. The use of a personalized, volumetric-based approach provided higher uptake and absorbed doses in hepatic metastases, with high objective response rates and effectively maintained systemic coverage.
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.
2026-08-02 | Safety of glucagon-like peptide-1 receptor agonists in neuroendocrine neoplasms.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been in use for 20 years. There have been concerns about their safety in patients with neuroendocrine neoplasms (NENs). The reports of GLP-1 receptor (GLP-1R)-driven proliferation of C-cell neoplasms in rodent studies had led to the black-box warning against their use in patients with medullary thyroid carcinoma or multiple endocrine neoplasia type 2. In this review, we have attempted to evaluate the physiological and pathological expression of GLP-1Rs in various endocrine organs and summarize the preclinical and clinical evidence regarding the effect of GLP-1RA exposure and risk of NENs. Glucagon-like peptide-1 receptor expression has not only been found in non-neoplastic tissues such as neurohypophysis, duodenal glands and pancreatic islets, but also in neuroendocrine tumors (NETs). Preclinical studies have demonstrated the proliferative effects of GLP-1RA in cell lines representing pancreatic NETs and small intestinal NETs. The available data from retrospective studies, randomized trials and cancer registries provide conflicting data and do not support a generalized increase in NENs with the use of GLP-1RA. Some epidemiological studies have even shown survival benefits associated with GLP-1RA use. In addition, significant gaps in evidence remain, such as lack of data regarding certain tumor subtypes, long-term prospective studies with NENs as the clinical endpoint and uncertainty regarding patients with multiple endocrine neoplasia type 1. Hence, the initiation of GLP-1RA therapy in patient with predisposition to NENs where a contraindication does not exist, should be approached cautiously with careful monitoring for long-term adverse effects.
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.
cell therapies
2026-09-30 | Controversies in NEN: An ENETS position statement on the role of liver transplantation (LT) in patients with advanced small-intestinal and pancreatic NETs.
Liver transplantation (LT) may offer survival or symptomatic benefit for highly selected patients with advanced, well-differentiated small-intestinal or pancreatic neuroendocrine tumours and unresectable liver-dominant metastases. However, its role remains controversial, as LT is rarely curative, recurrence is common, and benefits must be weighed against perioperative risk, lifelong immunosuppression, alternative therapies, and organ allocation ethics. This ENETS position statement summarises current evidence and expert consensus, reframing LT within a transplant-benefit model rather than fixed eligibility criteria. It outlines biologically informed selection principles and multidisciplinary assessment, as well as addressing the need for standardised characterisation, prospective registries, and long-term outcome data to better define the net clinical benefit of LT in this rare patient population.
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.
2026-03-09 | [Research progress on liver transplantation therapy for hepatic metastases in gastroenteropancreatic neuroendocrine tumors].
Neuroendocrine tumors are rare, low-grade malignant tumors with a gradually increasing incidence rate in recent years, with gastroenteropancreatic neuroendocrine tumors being the most common among them. The majority of gastropancreatic neuroendocrine tumors have already metastasized to the liver at the time of initial diagnosis; therefore, treatment targeting liver metastases is crucial. The most effective treatment for hepatic metastases of gastropancreatic neuroendocrine tumors is surgical resection. However, 60%-70% of patients are ineligible for radical resection due to diffuse liver involvement. Thus, an alternative treatment option offered for these patients is liver transplantation. Liver transplantation is considered an indication for well-differentiated, unresectable hepatic metastases of gastropancreatic neuroendocrine tumors because of the tumor's low invasiveness, slow growth, and the fact that the liver is often the only distant metastasis site. This article reviews the research progress of liver transplantation therapy for hepatic metastases in gastropancreatic neuroendocrine tumors.
2026-01-10 | Personalized Drug Screening and Risk Assessment in Patient-Derived Gastroenteropancreatic Neuroendocrine Neoplasms.
Precision medicine has transformed many areas in oncology. However, it remains largely unexplored in metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), where there is a need for further innovative therapies. To evaluate individual tumor responses to different agents, we have established a standardized personalized drug screening and risk assessment platform using patient-derived GEP-NEN primary cultures (n = 23, 16/23 from metastatic tumors, n = 12 small intestinal neuroendocrine tumors [siNETs], n = 10 pancreatic NETs [pNETs], n = 1 neuroendocrine carcinoma [NEC]). We assessed GEP-NEN primary culture cell viability, performed signaling pathway analysis by automated Western blotting and immunohistochemically evaluated tumor composition. Systematic drug testing of 27 agents including signaling inhibitors (i) (mechanistic target of rapamycin inhibitor [mTORi] everolimus, tyrosine kinase inhibitors cabozantinib/sunitinib, AKTi capivasertib, PI3Ki alpelisib, CDK4/6i ribociclib), DNA damage response inhibitors (PARPi niraparib, WEE1i adavosertib, ATRi berzosertib), chemotherapeutics (temozolomide, 5-fluorouracil, lurbinectedin), drug repurposed agents (zoledronic acid), and a personalized risk assessment (glucagon-like peptide [GLP]-2 analogue teduglutide, GLP-1 analogue semaglutide, sex hormones) was performed. We demonstrated statistically significant group effects and individualized responsiveness/resistance data. We identified differences in drug response between pNETs/siNETs and between GEP-NETs/GEP-NEC, respectively. We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.
2025-04-11 | Safety of loco-regional treatments in neuroendocrine liver metastases compared to an hepato-cellular carcinoma cohort: a single-center study.
Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) present with neuroendocrine liver metastases (NELM) in approximately 60% of the cases. Loco-regional interventional radiology procedures are widely used in the treatment of hepatocellular carcinoma (HCC) and have been increasingly used in recent years also in the setting of NELM. We aimed to assess the safety and, as a secondary aim, the local response of trans-arterial embolization (TAE) in NELM in our consecutive cohort of GEP-NEN patients. We collected data from all consecutive patients who underwent TAE for NELM secondary to GEP-NENs at IRCCS Humanitas Research Hospital, from March 2014 to February 2024. Safety and efficacy data were retrospectively collected. Short-term procedure-related adverse events (AE) were classified according to the new Society of Interventional Radiology classification. An internal analysis was also carried out on results from a cohort of patients with compensated advanced chronic liver disease complicated by HCC and treated with TAE. A total of 45 procedures in 21 patients were consecutively performed during the study period. Mean age at diagnosis was 56.6 years (SD 12.6) and median follow-up time was 60 months (range 10-169). At the time of treatment, the disease was bilobar in 19 cases (90.4%), with multifocal metastases present in 11 cases (52.3%). Adverse events were defined immediate (within 24 h from the procedure), early (within 30 days after the procedure), and late (> 30 days after the procedure). The rate of complications was 33.3% (N = 15), mostly comprising sepsis (73.3%, N = 11) which in 2 patients was secondary to the development of a perilesional abscess, requiring extended antibiotic therapy and, in one case, percutaneous drainage. Only one case of post-procedural bleeding was reported, which required further radiological embolization. Other less common AEs were reported, including acute post-procedural hepatitis, acute heart failure, and a generalized urticarial skin rash. The median length of hospitalization per procedure was 3 days (range 1-49). Only one tumor-related death was reported during the follow-up period. Disease stabilization or partial response was achieved in 86.6% (N = 39) of the procedures. In the HCC population a lower complication rate was observed: 6.10%, 5/82 patients: 3 were represented by liver abscess, one by acute-on-chronic liver failure and one by hepatic ischemia and consequent liver decompensation with ascites. 33 patients developed partial response (33/82, 40.24%). At one-year follow-up a 82.93% recurrence rate and a 1.22% mortality rate were detected. While loco-regional radiological treatments are recognized as safe and effective treatments for HCC, in the setting of NELM few data are available. In the current series TAE could represent a promising option for NELM treatment. The complication rate in NELM setting appears slightly higher than that reported both in the literature and in our own series for HCC treatment. Further studies are needed to fully assess TAE safety in NELM setting.
other
2026-07-04 | Epigenetic Dysregulation of Somatostatin Receptors (SSTR) 1-5 and Therapeutic Implications in Neuroendocrine and Non-Neuroendocrine Malignancies.
Somatostatin receptors (SSTR) mediate the antiproliferative, antisecretory, and proapoptotic effects of somatostatin and its synthetic analogs. Their surface expression on neuroendocrine tumor (NET) cells is required for somatostatin analog therapy and radiopharmaceutical therapy (RPT). However, 20%-30% of gastroenteropancreatic NETs and most poorly differentiated neuroendocrine carcinomas show insufficient SSTR expression, limiting therapeutic eligibility. Accumulating evidence indicates that reversible epigenetic mechanisms contribute substantially to SSTR loss, alongside tumor dedifferentiation, lineage-state changes, and clonal evolution with DNA hypermethylation of the SSTR2 promoter representing a central event, complemented by chromatin remodeling and non-coding RNA-mediated regulation. Preclinical studies demonstrate that epigenetic therapies, including DNA methyltransferase and histone deacetylase inhibitors, can restore functional SSTR expression. Notably, the first-in-human LANTana trial provides clinical proof-of-concept that epigenetic priming with oral decitabine/cedazuridine can induce SSTR2 re-expression and enable subsequent RPT in receptor-negative tumors. This review synthesizes current knowledge of epigenetic regulation across all five SSTR subtypes (SSTR1-SSTR5), examines receptor silencing in neuroendocrine and non-neuroendocrine malignancies, and critically evaluates the preclinical and clinical evidence supporting therapeutic strategies that target these mechanisms.
2025-11-14 | Data from Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A Multicohort, Basket, Phase II Trial (CABATEN/GETNE-T1914)
<div>AbstractPurpose:<p>Multikinase inhibitors have shown efficacy in endocrine neoplasms, and synergism with immune checkpoint inhibitors has been noted in other tumors.</p>Patients and Methods:<p>This is a prospective, multicenter, open-label, Simon two-stage optimal design, phase II study including patients with advanced and refractory endocrine and neuroendocrine neoplasms in six cohorts: lung well-differentiated neuroendocrine tumors, anaplastic thyroid cancer (ATC), adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET), and grade 3 extrapulmonary neuroendocrine neoplasms. Patients received atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 40 mg/day orally until disease progression or unacceptable toxicity. The primary objective was the overall response rate (ORR) by RECIST 1.1.</p>Results:<p>From October 2020 to December 2022, 93 patients were included. The ORR was 14.3% [95% confidence interval (CI), 1.8–42.8] in ATC (<i>N</i> = 14); 8.3% (95% CI, 1.0–27.0) in ACC (<i>N</i> = 24); 15.4% (95% CI, 1.9–45.5) in PPGL (<i>N</i> = 13), and 16.7% (95% CI, 4.7–37.4) in GEP-NET (<i>N</i> = 24). Lung well-differentiated neuroendocrine tumors and grade 3 extrapulmonary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in PPGL, and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6% and 47.6%, respectively. No unexpected toxicity was observed.</p>Conclusions:<p>Cabozantinib and atezolizumab were safely administered and showed promising ORR, and preliminary long-term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.</p></div>
2025-05-20 | Impact of multikinase inhibitors in reshaping the treatment of advanced gastroenteropancreatic neuroendocrine tumors.
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.
2025-04-18 | Investigation of an oncolytic herpes simplex virus as a potential therapeutic agent for gastroenteropancreatic neuroendocrine neoplasms.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) present unique challenges due to their heterogeneity and limited treatment options. Oncolytic virotherapy has emerged as a promising therapeutic for other NETs and thus, we sought to investigate the potential of an engineered oncolytic herpes simplex virus (oHSV), M002, for GEP-NETS. We employed an established long-term passage GEP-NET cell line and a unique, human pediatric patient-derived xenograft GEP-NET line. We found the virus to effectively infect, replicate within, and kill both cell lines in vitro. Similar effects were noted in vivo, with M002 decreasing tumor growth and improving overall survival in mice bearing tumors from both the established cell line and human GEP-NET PDX. Overall, these studies provide an evaluation of an oncolytic HSV in GEP-NETs, highlighting its therapeutic potential and considerations for clinical translation.
2025-04-10 | Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors with limited treatment options. This phase 2 Bayesian study evaluated the combination of regorafenib, a multikinase inhibitor, and avelumab, a programmed death 1 (PD1) ligand 1 inhibitor, in advanced grade 2-grade 3 well-differentiated GEP neuroendocrine tumors or grade 3 GEP neuroendocrine carcinomas after progression on prior therapies. A total of 47 participants were enrolled and 42 were evaluable for efficacy. Participants received regorafenib (160 mg per day) and avelumab (10 mg kg-1 biweekly) in 28-day cycles. The primary endpoint, 6-month objective response rate per the response evaluation criteria in solid tumors version 1.1, was 18% (95% confidence interval (CI): 8-31%), with a median progression-free survival of 5.5 months (95% CI: 3.6-8). Durable responses were noted (16.6 months; 95% CI: 3.7-no response). Treatment-related adverse events were manageable, with fatigue, diarrhea and palmar-plantar erythrodysesthesia being most common. Exploratory biomarker analysis identified PD1 and indoleamine 2,3-dioxygenase 1 expression and activity as potential resistance markers. These findings highlight the clinical potential of regorafenib and avelumab in GEP-NENs, emphasizing the need for predictive biomarkers and validation in future randomized trials. Clinical Trial registration: NCT03475953 .
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Drug Discovery Landscape
22 orphan drug designations for Gastroenteropancreatic neuroendocrine neoplasm, including 6 approved therapies.
22 orphan drug designations for Gastroenteropancreatic neuroendocrine neoplasm, including 6 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
225Ac-Dotatate | peptides | FDA | RayzeBio, Inc. | |
Lead (212Pb) bamzireotide navoxetan | peptides | EMA | Eusme Limited | |
Lutetium-177(3+),S2,S7-cyclo[N-{4,7,10-tricarboxymethyl-1,4,7,10-tetraaza-cyclododecan-1-yl-acetyl}-4-chloro-L-phenylalanyl-D-cysteinyl-4-[(4S)-2,6-dioxo-1,3-diazinane-4-carboxamido]-L-phenylalanyl-4-(carbamoylamino)-D-phenylalanyl-L-lysyl-L-threonyl-L-cysteinyl-D-tyrosinamide] | small molecules | EMA | — | Ariceum Therapeutics GmbH |
FOSBRETABULIN TROMETHAMINE | small molecules | EMA | Diamond Pharma Services Ireland Limited | |
Ceclazepide | small molecules | EMA | — | Yes Pharmaceutical Development Services GmbH |
lutetium (177Lu)-edotreotide | peptides | FDA | ITM Solucin GmbH | |
Gallium (68Ga)-edotreotide [SomaKit TOC] | peptides | EMA | Approved | Novartis Europharm Limited |
satoreotide tetraxetan | peptides | FDA | Ariceum Therapeutics GmbH | |
Lutetium (177Lu) edotreotide | peptides | EMA | ITM Solucin GmbH | |
68Ga-2,2'-(7-(4-((S)-1-((4S,7S,10S,13R,16S,19R)-4-((R)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylcarbamoyl)-10-(4-aminobutyl)-16-(4-((S)-2,6-dioxohexahydropyrimidine-4-carboxamido)benzyl)-7-((R)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-13-(4-ureidobenzyl)-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19-ylamino)-3-(4-chlorophenyl)-1-oxopropan-2-ylamino)-1-carboxy-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid | other | EMA | Ariceum Therapeutics GmbH | |
Gallium [Ga-68]-N-[(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-Lcysteinyl-L-threonine-cyclic(2-7)disulfide | other | EMA | Advanced Accelerator Applications | |
Gallium (68Ga)-pasireotide tetraxetan | small molecules | EMA | — | OctreoPharm Sciences GmbH |
lutetium Lu 177 dotatate [Lutathera] | peptides | FDA | Approved | Advanced Accelerator Applications |
lutetium Lu 177 dotatate [Lutathera] | peptides | FDA | Approved | Advanced Accelerator Applications |
lutetium Lu 177 dotatate | peptides | FDA | Approved | Advanced Accelerator Applications |
lutetium Lu 177 dotatate [Lutathera] | other | FDA | Approved | Advanced Accelerator Applications |
Yttrium (90Y) edotreotide [Onalta 90Y edotreotide] | peptides | EMA | [INACTIVE] Molecular Insight Limited | |
Lutetium (177Lu)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide [Lutathera] | peptides | EMA | Approved | Novartis Europharm Limited |
Everolimus [Afinitor] | small molecules | EMA | Novartis Europharm Limited | |
Edotreotide | other | FDA | Molecular Insight Pharmaceuticals, Inc. (Progenics Subsidiary) | |
Multi-ligand somatostatin analog | peptides | FDA | Novartis Pharmaceuticals Corporation | |
Pasireotide | small molecules | EMA | Novartis Europharm Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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