Gastroenteropancreatic Neuroendocrine Tumors Research Articles

Gastroenteropancreatic neuroendocrine tumors in children and adolescents.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare in children and adolescents. Standard management of these tumors has not been well established due to their rarity in this age group. We aimed to report the clinical and pathological characteristics of patients with this rare disease followed and treated between the years 1993-2022. The medical records of patients with GEP-NETs were reviewed. Fourteen patients (11 girls, 3 boys) were diagnosed with GEP-NET. The median age was 13 (9-18) years. Tumor localization was the appendix in 12, stomach in one and pancreas in one patient. Mesoappendix invasion was detected in four patients two of whom underwent right hemicolectomy (RHC) and lymph node dissection (LND). Of those, one patient had lymph node involvement. The other two had not further operations. Somatostatin was used in one with pancreatic metastatic disease and the other with gastric disease after surgery. No additional treatment was given in other patients. All patients are under follow-up without evidence of disease at a median follow-up of 85 months (7-226 months). GEP-NETs should be considered in the differential diagnosis of acute appendicitis and in cases with persistent abdominal pain. In children, there is invariably a favorable prognosis, and additional surgical interventions other than simple appendectomies generally do not provide benefits. Mesoappendix invasion may not necessitate RHC and LND.

Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors

BackgroundPediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway. MethodsWe utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition. ResultsWe found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis. ConclusionsThe results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.

Interest of Integrated Whole-Body PET/MR Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms: A Retro-Prospective Study.

Simultaneous positron emission tomography/magnetic resonance imaging (PET-MRI) combines the high sensitivity of PET with the high specificity of MRI and is a tool for the assessment of gastroenteropancreatic neuroendocrine neoplasms (G-NENs). However, it remains poorly evaluated with no clear recommendations in current guidelines. Thus, we evaluated the prognostic impact of PET-MRI in G-NEN patients. From June 2017 to December 2021, 71 G-NEN patients underwent whole-body PET-MRI for staging and/or follow-up purposes. A whole-body emission scan with 18F-6-fluoro-L-dihydroxyphenylalanine (18FDOPA, n = 30), 18F-fluoro-2-deoxy-D-glucose (18FDG, n = 21), or 68Ga-(DOTA(0)-Phe(1)-Tyr(3))-octreotide (68Ga-DOTATOC, n = 20) with the simultaneous acquisition of a T1-Dixon sequence and diffusion-weighed imaging (DWI), followed by a dedicated step of MRI sequences with a Gadolinium contrast was performed. The patients underwent PET-MRI every 6-12 months during the follow-up period until death. Over this period, 50 patients with two or more PET-MRI were evaluated. The mean age was 61 [extremes, 31-92] years. At the baseline, PET-MRI provided new information in 12 cases (17%) as compared to conventional imaging: there were more metastases in eight, an undescribed location (myocardia) in two, and an unknown primary location in two cases. G grading at the baseline influenced overall survival. During the follow-up (7-381 months, mean 194), clinical and therapy managements were influenced by PET-MRI in three (6%) patients due to new metastases findings when neither overall, nor disease-free survivals in these two subgroups (n = 12 vs. n = 59), were different. Our study suggests that using PET/MRI with the appropriate radiotracer improves the diagnostic performance with no benefit on survival. Further studies are warranted to evaluate the cost-effectiveness of this procedure.

Gastroenteropancreatic neuroendocrine neoplasms-Surgery in amultimodal concept

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are mainly found in the small intestine and pancreas. The course of the disease in patients is highly variable and depends on the degree of differentiation (G1-G3) of the neoplasm. The potential for metastasis formation of GEP-NEN is high even with good differentiation (G1). Lymph node metastases and, in many cases, liver metastases are also often found. Less common are bone metastases or peritoneal carcinomas. The treatment of these GEP-NENs is surgical, whenever possible. If an R0resection with removal of all lymph node and liver metastases is successful, the prognosis of the patients is excellent. Patients with diffuse liver or bone metastases can no longer be cured by surgery alone. The long-term survival of these patients is nowadays possible due to the availability of drugs (e.g., somatostatin analogues, tyrosine kinase inhibitors), peptide receptor radionuclide therapy (PRRT) and liver-directed procedures, with agood quality of life.

NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P<0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

Hypoxia drives CBR4 down-regulation promotes gastroenteropancreatic neuroendocrine tumors via activation mammalian target of rapamycin mediated by fatty acid synthase.

Hypoxia has been highly proven a hallmark of tumor micro-environment, promoting the malignant phenotypes, playing a crucial role from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Increasing evidence also showed that hypoxia mediated the abnormal lipid metabolism in cancer by regulating various oncogenic signal pathways. However, it is still unclear but attractive how hypoxia specifically functioned and changed the condition of the tumor micro-environment. In present study, we find that hypoxia promoted the methylation degree of CBR4 promoter region thus downgraded the expression of CBR4, which promoted GEP-NETs progression and increased the sensitivity of GEP-NETs cells to everolimus. Further, CBR4 interacted with fatty acid synthase (FASN), displaying a down-regulation of FASN by activating the ubiquitin proteasome pathway and suppressed mTOR signaling. Overall, our results uncovers the CBR4/FASN/mTOR axis as a mechanism for tumor development and inspires us a new molecular guide for the therapeutic strategies for GEP-NETs treatment.

177 Lu-DOTATATE PRRT Safety and Organ-at-Risk Dosimetry in Patients With Gastroenteropancreatic Neuroendocrine Tumors : Data From the Prospective Phase 2 LUMEN Study.

The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177 Lu-DOTATATE. Thirty-seven patients with GEP-NETs underwent 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% ( P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. This study confirms the safety profile of 177 Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.

TRLS-10. CLINICAL TRIAL IN PROGRESS - CONNECT2007: PHASE I/II STUDY OF LUTATHERA IN PATIENTS WITH RECURRENT AND/OR PROGRESSIVE HIGH-GRADE CENTRAL NERVOUS SYSTEM (CNS) TUMORS AND MENINGIOMAS THAT DEMONSTRATE UPTAKE ON DOTATATE PET

Abstract BACKGROUND Somatostatin type-2A receptors (SST2A) regulate cell growth through complex downstream modulation of proliferation and apoptosis signaling, thereby representing a potential therapeutic target. Lutetium (177Lu-DOTATATE), a radionuclide therapy which binds SST2A and delivers local radiation via beta particle emission, gained FDA approval for gastroenteropancreatic neuroendocrine tumors, a disease characterized by SST2A expression. Potential expansion of Lutathera into pediatric neuro-oncology is supported by evidence that medulloblastoma, other embryonal tumors, and meningiomas consistently express membranous SST2A, exhibit corresponding uptake on SST2A-radiolabeled nuclear imaging (DOTATATE PET), and have demonstrated radiographic response to SST2A-targeted therapy, suggesting sufficient CNS penetration to achieve therapeutic benefit. METHODS CONNECT2007 (NCT05278208) is an international, multicenter phase I/II study investigating safety and efficacy of Lutathera in children and adults with SST2A-expressing CNS tumors. Patients with recurrent/progressive high-grade CNS tumors and meningiomas can undergo screening, consisting of DOTATATE PET imaging for functional confirmation of SST2A expression, requiring adequate uptake (Krenning score ≥2) by central review. The phase I cohort will enroll patients aged 4-&amp;lt;12 years to determine the pediatric recommended phase II dose (RP2D) following a Rolling Six design, with three potential dose levels, starting at the adult RP2D (200mCi), scaled by body surface area. The phase II cohort will enroll patients aged ≥12 years to assess anti-tumor activity through evaluation of 6-month progression-free survival in medulloblastoma/embryonal tumors (descriptive in other histologies). Lutathera is administered intravenously, with concurrent amino acids for nephroprotection, dosed every 8 weeks for up to 4 cycles. Longitudinal correlative studies include 1) evaluating prevalence, heterogeneity, and clinical, histologic molecular, and radiographic predictors of SST2A expression, 2) characterizing radiation dosimetry of Lutathera in organs at risk of toxicity and within CNS to assess tumor penetration, and 3) identifying imaging and molecular biomarkers of response. Enrollment began in January 2023; both cohorts remain open to accrual.

Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors

IntroductionThe incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied.Materials and MethodsRetrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS).ResultsOf the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017).ConclusionA higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.

A reassessment of the clinical utility of 68Ga-DOTATATE PET/CT in patients with gastroenteropancreatic neuroendocrine tumors.

e16294 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and biologically diverse group of tumors that can be challenging to image. Gallium-68 (Ga-68) DOTATATE positron emission tomography/computed tomography (PET/CT) is the most sensitive imaging tool for these tumors and has now been in clinical practice for over a decade. While its use has increased over time, its clinical impact remains unclear for specific stages of disease and indications for imaging. We sought to investigate this to provide information to guide its future use in clinical management. Methods: This retrospective cohort study identified adults with pathologically confirmed GEP-NETs between 1/1/2020 and 9/1/2022 at a tertiary care academic medical center. The electronic medical record was reviewed for demographic, clinical, and radiographic data. The primary objective was to determine if the use of 68Ga-DOTATATE PET/CT was associated with a change in clinical management, medical or surgical. The secondary objective was to determine if 68Ga-DOTATATE PET/CT was more effective in identifying primary or metastatic lesions compared to traditional imaging such as CT or magnetic resonance imaging (MRI) performed less than 90 days of the PET/CT scan. Percentages are reported with 95% Confidence Intervals (CI). Results: Overall, 124 patients with pathologically confirmed GEP NETs underwent a total of 207 68Ga-DOTATATE PET/CT scans. The majority (92.7%) of GEP NETs were moderately/well differentiated and the primary sites included the small intestine (50%), pancreas (23.4%), appendix/colon (8.9%), gastric (8.1%), mesentery (2.4%), and unknown (7.3%). Following PET/CT scan, 51 patients (41.1%; 95% CI = 32.4-49.8) had a change in clinical management, with the proportion of patients who had a change being higher among those with metastatic disease (44.9% vs 14.5%). Of the 124, 72 patients had traditional imaging 90 days or less prior to PET/CT available for comparison. In this subgroup, 34 patients (47.2%; 95% CI = 35.7-58.7) had new lesions identified on PET/CT that were not identified using traditional imaging and of the 34 patients with new lesions identified, 79.4% (95% CI = 66-93) had a change in their clinical management. The majority of these patients had M1 disease (50% vs 15.4%). Conclusions: This study highlights the impact of 68Ga-DOTATATE PET/CT imaging in the clinical management of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs). Notably this imaging technique resulted in a change in clinical management for 41% of these patients, particularly benefiting those with metastatic (M1) disease, where the change in management was more pronounced (44.9% vs. 14.5%). Furthermore, 68Ga-DOTATATE PET/CT proved superior to traditional imaging revealing new lesions in 47.2% of the patients, with the majority being patients with metastatic disease.

Safety and time to response of [177Lu]Lu-DOTATATE in patients with newly diagnosed advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Sub-analysis of the phase 3 randomized NETTER-2 study.

4131 Background: NETTER-2 (NCT03972488) is the first randomized study to evaluate radioligand therapy ([177Lu]Lu-DOTA-TATE; hereafter 177Lu-DOTATATE) at first line (1L) in patients (pts) with advanced, well-differentiated higher grade (G2 and G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Significant improvements in progression-free survival and objective response rate (ORR) were observed for pts receiving 177Lu-DOTATATE. This sub-analysis of NETTER-2 assessed safety and time to response (TTR). Methods: Eligible pts (n=226) were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki67 ≥10% and ≤55%) advanced GEP-NETs and were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq every 8 weeks [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during 177Lu-DOTATATE treatment then Q4W (177Lu-DOTATATE arm), or 60 mg octreotide LAR Q4W (control arm). Hematologic adverse events (AEs) and laboratory toxicities were scored according to CTCAE grade. Response was assessed centrally based on conventional imaging (RECIST 1.1 criteria). Results: The AE pattern in the 177Lu-DOTATATE arm was consistent with the established safety profile. Among laboratory abnormalities, grade 3/4 decreases in lymphocytes (38.1% vs 2.7%), leukocytes (4.1% vs 0), neutrophils (3.4% vs 0), platelets (2.0% vs 0) and hemoglobin (1.4% vs 2.7%) were observed in 177Lu-DOTATATE (n=147) and control (n=73) arms, respectively; median time to first occurrence of hematologic toxicities was 4.4 months among pts with immediate hematotoxicities. These events were transient and manageable. There was no notable difference in infection rates between treatment arms (31.3% 177Lu-DOTATATE and 27.4% control). One case of myelodysplastic syndrome was observed (177Lu-DOTATATE arm ~14 months after first cycle). Five fatal AEs occurred during the randomized treatment period; all considered unrelated to treatment and attributed to GEP-NET progression. AEs leading to 177Lu-DOTATATE dose interruption, reduction and discontinuation occurred in 14 (9.5%), 2 (1.4%) and 3 (2.0%) pts, respectively. Among 65 responders in the 177Lu-DOTATATE arm (ORR 43 %), median TTR (Q1, Q3) was 5.7 months (4.1, 8.3). Most responses occurred during the 4-cycle treatment with 177Lu-DOTATATE. Conclusions: In pts with advanced G2 and G3 (Ki67 ≥10% and ≤55%) GEP-NETs treated with 177Lu-DOTATATE at 1L the most common hematologic toxicity was lymphopenia, but infection rates were similar vs control. With a median TTR of 5.7 months, most responses to 177Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177Lu-DOTATATE and supports its use at 1L for this pt population. Clinical trial information: NCT03972488 .

[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study

There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

224P Genomic patterns and clinical implications in gastroenteropancreatic neuroendocrine neoplasms

224P Genomic patterns and clinical implications in gastroenteropancreatic neuroendocrine neoplasms

The factors associated with all-cause in-hospital mortality in patients with malignant well-differentiated gastroenteropancreatic neuroendocrine tumors: A retrospective analysis of National Inpatient Survey (NIS) 2020 dataset.

e16292 Background: Neuroendocrine tumors (NET) affect less than 200,000 (52 per 100,000) of the US population, with malignant well-differentiated gastroenteropancreatic (GEP) NETs accounting for about 65% of the cases. Owing to its rarity, the evidence on factors associated with all-cause mortality is limited. To address this gap, this study aims to identify socio-demographic and clinical factors associated with all-cause in-hospital mortality for patients with malignant well-differentiated GEP NET. Methods: We analyzed data from 2020 Nationwide Inpatient Sample survey on patients hospitalized with malignant well-differentiated GEP NET. Using ICD10 code, we identified patients hospitalized with any diagnosis of malignant well-differentiated GEP NET. In-hospital mortality was assessed based on the patient final disposition on discharge and dichotomized. Exposure variables analyzed included age, sex, tumor site, history of essential hypertension, COVID-19, hyperlipidemia, insurance status, length of hospital stay, and number of comorbidities present on the patients record. Multivariable logistic regression was used to assess for factors associated with mortality. Results: Of the 956 patients in this study, most were white (73.43%), male (48.28%) and mean age was 65 years (SD 13.59). Affected sites include small intestine (57.25%), pancreas (13.56%), colon (8.47%), appendix (8.26%), stomach (8.68%) and rectum (3.51%). Our results revealed that females were less likely to die in the hospital compared to their male counterpart hospitalized with malignant well-differentiated GEP NET (aOR = 0.42; 95% CI: 0.19 - 0.95). The presence of hyperlipidemia was significantly associated with in-hospital mortality (aOR = 0.24; 95% CI: 0.08 - 0.75). For every unit increase in the number of comorbidities, there is 12% increased risk of mortality (aOR = 1.12; 95% CI: 1.05 -1.19). The associations of age, race, tumor site, history of hypertension, insurance status or length of stay with in-hospital mortality were not statistically significant. Conclusions: Our study found significant associations of sex, hyperlipidemia, number of comorbidities and in-hospital mortality among patients with malignant well-differentiated GEP NET. Findings from this study highlight that factors such as sex, hyperlipidemia and number of comorbidities may be critical when developing prognostic tools that can be used to determine the risk of mortality among hospitalized patients hospitalized with these tumors.

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

3091 Background: RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Herein, we report updated results from the phase Ib portion of the trial. Methods: The phase Ib portion of the trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level –1 90 kBq/kg; Level –2 60 kBq/kg. DLT was assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1. Results: 17 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n=5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented. Conclusions: RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 .

A phase II randomized control trial of triapine plus lutetium 177 DOTATATE versus lutetium 177 DOTATATE alone for well-differentiated somatostatin receptor-positive neuroendocrine tumors.

TPS4202 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium 177 DOTATATE (Lutathera) is a beta-emitting radionuclide, FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 14% ORR. Peptide receptor radionuclide therapy (PRRT) also doesn’t seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals. Methods: This study is an investigator initiated, NCI sponsored, multicenter randomized phase 2 trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive neuroendocrine tumor. A total of 94 patients will be equally randomized to either Lu-177 dotatate or Triapine + Lu-177 dotatate arm. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Triapine will be administered orally from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate overall response rate (ORR). Secondary endpoint is to evaluate median PFS. We are also evaluating triapine PK, plasma deoxyribonucleosides, circulating DNA and plasma hPG80, a novel blood based diagnostic biomarker. Clinical trial information: 05724108.

212P A phase II study of cabozantinib and temozolomide in advanced progressive gastroenteropancreatic or lung neuroendocrine tumors (NETs)

212P A phase II study of cabozantinib and temozolomide in advanced progressive gastroenteropancreatic or lung neuroendocrine tumors (NETs)

Claims-based analysis of treatment practices of patients with metastatic gastroenteropancreatic neuroendocrine tumors (mGEP-NET) in the USA.

e16286 Background: GEP-NET is a rare disease with variable tumor biology. An indolent disease course with subtle symptoms renders timely diagnosis difficult; 2/3 of patients (pts) are diagnosed at locally advanced or metastasized stage. In clinical decision-making, disease-specific factors, patient (pt) age and long-term disease control must be balanced against the aggressiveness of therapies. NCCN, NANETS and ENETS guidelines recognize the diversity of mGEP-NET by recommending individualized treatment approaches. We aimed to describe treatment (Tx) utilization patterns in mGEP-NET. Methods: Retrospective cohort study using MarketScan® Commercial and Medicare Databases spanning 07/01/2017-01/31/2023. Eligible were GEP-NET pts with ≥1 inpatient or ≥2 outpatient claims, a subsequent new diagnosis of metastatic disease (index), no secondary malignancy, and follow-up time of ≥12 months (m) after index. Results: Of 16218 GEP-NET pts, 2002 (mean age 60y; 50% female) met inclusion criteria. Mean follow-up time after index was 17m, with 49%, 27% and 15% followed up for ≥12, 24 and 36m, resp. Medical history (12m baseline before index) included mean Charlson Comorbidity Index of 2.62, with hypertension (HTN), type 2 diabetes (T2DM), chronic liver disease (CLD), asthma/COPD, cardiovascular disease (CVD), and chronic kidney disease (CKD) present in 56, 26, 22, 18, 17 and 10% of pts, resp.; 5% had carcinoid syndrome. In total, 949 pts (47.4%) received first-line (1L) systemic Tx: somatostatin analogs (SSA; 61.6%) of either very short or long duration (median 116d vs 775d), chemotherapy (38.8%), targeted therapies (3.4%) and PRRT (0.5%). Relative to NCCN cancer surveillance guidelines, 49.5% received more and 36.8% received fewer than 4 scans in the first year of treatment. Conversely, 1053 (52.6%) did not receive any 1L systemic Tx. With the exception of CLD, pts with vs without 1L Tx had similar proportions of medical conditions during the 12m baseline and during follow-up (HTN 72.4 vs 66.5%; T2DM 34.0 vs 30.3%; asthma/COPD 16.5 vs 19.3%; CVD 27.3 vs 36.9%; CKD 18.9 vs 17.9%; however, CLD 54.0 vs 36.7%). See Table comparing both cohorts on insurance, treatments, and health care utilization during follow-up. Conclusions: This claims analysis reveals treatment differences among mGEP-NET pts that cannot be explained by the parameters assessed herein. Further research should investigate factors influencing diagnosis and treatment decision-making, applying also pt-level health record data; and analyze economic barriers to diagnosis and treatment. [Table: see text]

Safety, tolerability and efficacy of 212Pb-DOTAMTATE as a targeted alpha therapy for subjects with unresectable or metastatic somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors (SSTR+ GEP-NETs): A phase 2 study.

4020 Background: 212Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide Therapy (PRRT) with beta-emitters like 177Lu-DOTATATE, currently considered the standard of care for subjects with GEP-NETs. Methods: ALPHAMEDIX 02 is a Phase II, open-label, multicenter study evaluating the safety, tolerability and efficacy of 212Pb-DOTAMTATE in PRRT-naïve (Cohort 1, N = 36) and PRRT-refractory (Cohort 2, Target N = 30) subjects with histologically confirmed unresectable or metastatic GEP-NETs, positive somatostatin analogue imaging and at least 1 site of measurable disease per RECIST 1.1. 212Pb-DOTAMTATE was administered at 67.6 μCi/kg per cycle, with a maximum activity administered per cycle of 5.5 mCi every 8 weeks, for up to 4 cycles. Primary endpoints include overall response rate (ORR) per RECIST1.1, and incidence and severity of adverse events (AEs). Secondary endpoints include progression free survival, overall survival , and health-related quality of life. Initial results of the already completed cohort 1 are presented. Results: In cohort 1, 17 out of 36 subjects with metastatic SSTR+ GEP-NETs achieved a confirmed response (ORR 47.2% (32.0-63.0%)). In the Phase I trial, five out of eight PRRT- naïve subjects with SSTR+ GEP-NETs treated with the same regimen of 212Pb-DOTAMTATE achieved a response (ORR 62.5% (30.6-86.3%)): the combined ORR from both studies is 50% (22 out of 44, 95%-CI:36% - 64%). Median Duration of Response (DOR) has not been reached in both studies. Four out of five subjects (80%) with confirmed response in Phase I had a DOR of ≥ 12 months. In the ongoing Phase II study the response follow-up for 10 subjects with confirmed response is currently shorter than 6 months: so far 7 out of 17 subjects (41%) with confirmed response had a DOR of ≥ 6 months, and one of these subjects had a DOR of ≥ 12 months. Lymphocytopenia is a lead cause of the 59% grade 3 and 4 AEs reported in subjects in cohort 1. Overall, 4 fatal AEs were reported: death / progressive disease (N = 2), carcinoid syndrome (N = 1) and sepsis (N = 1). Conclusions: In PRRT-naïve subjects with SSTR+ unresectable or metastatic GEP-NETs treatment with up to 4 cycles of ²¹²Pb-DOTAMTATE (67.6 μCi/kg/cycle) was well-tolerated, with a safety profile consistent with the underlying disease and expected toxicities of radioligand therapy, similar to 177Lu-DOTATATE. The ORR of 47.2% in cohort 1 (50% in the pooled dataset) appears to be substantially higher than the ORR previously reported for 177Lu-DOTATATE in the pivotal NETTER-1 study (ORR 18% (10–25%)). Clinical trial information: NCT05153772 .