Metastatic GEP-NET Research Articles

Impact of primary tumor resection in the management of metastatic well-differentiated neuroendocrine tumors of the small bowel and pancreas.

Patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET) often present with advanced disease. Primary tumor resection (PTR) in the setting of unresectable metastatic disease is controversial. Most studies evaluating the impact of PTR on overall survival (OS) have been performed using large population-based databases, with limited treatment related data. This study aims to determine whether PTR improves OS and progression-free survival (PFS) in patients with metastatic well-differentiated GEP-NET. This is a retrospective single-institution study of patients with metastatic well-differentiated GEP-NET between 1978 and 2021. The primary outcome was OS. The secondary outcome was PFS. Chi-squared tests and Cox regression were used to perform univariate and multivariate analyses (MVA). OS and PFS were estimated using the Kaplan-Meier method and log-rank test. Between 1978 and 2021, 505 patients presented with metastatic NET, 151 of whom had well-differentiated GEP-NET. PTR was performed in 31 PNET and 77 SBNET patients. PTR was associated with improved median OS for PNET (136 vs. 61 months, p = .003) and SBNET (not reached vs. 79 months, p<.001). On MVA, only higher grade (HR 3.70, 95%CI 1.49-9.17) and PTR (HR 0.21, 95%CI 0.08-0.53) influenced OS. PTR resulted in longer median PFS for patients with SBNET (46 vs. 28 months, p = .03) and a trend toward longer median PFS for patients with PNET (20 vs. 13 months, p = .07). In patients with metastatic well-differentiated GEP-NET, PTR is associated with improved OS and may be associated with improved PFS and should be considered in a multidisciplinary setting. Future prospective studies are needed to validate these findings.

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 .

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

Experience with 177Lu-Dotatate in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors at a Single Urban Cancer Center

177Lu-Dotatate is an FDA approved peptide receptor radiotherapeutic (PRRT) agent for metastatic well differentiated midgut neuroendocrine tumors (NETs). Questions remain regarding tolerability in diverse subpopulations with higher grade disease, more than one prior line of treatment, and in non-ileal primaries. In this retrospective analysis, we review the outcomes of patients with histologically proven metastatic GEP-NETs who received 177Lu-Dotatate at a single racially diverse urban cancer center. Treated patients had disease that progressed on systemic therapy. Uptake at disease sites was demonstrated in all patients using 68-Gallium-Dotate PET/CT. ECOG performance score (PS) was 0 to 2. 177Lu-Dotatate was administered in 200 mCi doses every 8 weeks for a total of 4 cycles and a maximum of 800 mCi. Patients were followed with serial CT scan and/or abdominal MRI with best objective response assessed per RECIST criteria. Fifty-one patients were treated between December 2017 and September 2021. 42 patients completed a minimum 3-month follow-up imaging. Median age was 66 years, 59% were female, 66% identified as white, 26% as Black, 8% as other or chose not to specify. Most frequent primary site was small intestine (69%). All had metastatic disease involving the liver except for one. Median time from diagnosis to 177Lu-Dotatate was 51 months. Time from first line therapy to first 177Lu-Dotatate was 3.65 years CTCAE grade 3/4 hematologic toxicity was seen in 6 of 51 patients (12%) of patients. Grade 3/4 thrombocytopenia occurred in 3 pts, grade 3/4 leukopenia occurred in 2 pts and grade 3 anemia occurred in 1 patient. One patient developed myelodysplastic syndrome 1 year after first 177Lu-Dotatate. Patients who identified as non-white did not experience significantly higher rate of toxicity. Of the 42 patients who reached 3-month follow-up 29% had a partial response, 45% had a mixed or stable response, and 36% had progressive disease. Only gender demonstrated significant difference; with male gender associated with worse response categories (p = 0.001). Median overall survival (OS) was 2.13 years. Metastatic disease in the liver only (p = 0.013), tumor grade > 1 (p = 0.027), and no history of surgery (p = 0.011) were associated with significantly worse OS. The median progression free survival (PFS) was 1.56 years. Patients of male gender (p = 0.037), with liver only metastases (p = 0.013), and with higher grade tumors (p = 0.024) had worse PFS. There was no difference in PFS by race, primary tumor site (pancreatic vs small bowel), performance status, or prior treatment history. In this retrospective study, investigating a racially and socioeconomically diverse patients, we report similar toxicity to prior studies investigating 177Lu-Dotatate. Despite similar toxicity, median PFS and OS were inferior to reported outcomes in NETTER-1 which we suspect may be partly due to timing of treatment and differences in patient populations.

Circulating hsa-miR-5096 predicts 18F-FDG PET/CT positivity and modulates somatostatin receptor 2 expression: a novel miR-based assay for pancreatic neuroendocrine tumors.

Whole miRNOme NGS profiling was conducted on plasma samples obtained from well-differentiated advanced, metastatic, inoperable G1, G2 and G3 GEP-NET patients enrolled in the non-randomized LUX (NCT02736500) and LUNET (NCT02489604) clinical trials prior to PRRT (screening set, n= 24). Differential expression analysis was performed between 18F-FDG positive (n=12) and negative (n=12) patients. Validation was conducted by Real Time quantitative PCR in two distinct well-differentiated GEP-NET validation cohorts, considering the primary site of origin (PanNETs n=38 and SINETs n=30). The Cox regression was applied to assess independent clinical parameters and imaging for progression-free survival (PFS) in PanNETs. In situ RNA hybridization combined with immunohistochemistry was performed to simultaneously detect miR and protein expression in the same tissue specimens. This novel semi-automated miR-protein protocol was applied in PanNET FFPE specimens (n=9). In vitro functional experiments were performed in PanNET models. While no miRNAs emerged to be deregulated in SINETs, hsa-miR-5096, hsa-let-7i-3p and hsa-miR-4311 were found to correlate with 18F-FDG-PET/CT in PanNETs (p-value:<0.005). Statistical analysis has shown that, hsa-miR-5096 can predict 6-month PFS (p-value:<0.001) and 12-month Overall Survival upon PRRT treatment (p-value:<0.05), as well as identify 18F-FDG-PET/CT positive PanNETs with worse prognosis after PRRT (p-value:<0.005). In addition, hsa-miR-5096 inversely correlated with both SSTR2 expression in PanNET tissue and with the 68Gallium-DOTATOC captation values (p-value:<0.05), and accordingly it was able to decrease SSTR2 when ectopically expressed in PanNET cells (p-value:<0.01). hsa-miR-5096 well performs as a biomarker for 18F-FDG-PET/CT and as independent predictor of PFS. Moreover, exosome-mediated delivery of hsa-miR-5096 may promote SSTR2 heterogeneity and thus resistance to PRRT.

The tumor mutation burden in gastro-entero-pancreatic-neuroendocrine tumors.

654 Background: Neuroendocrine tumors (NET) are rare tumors with limited treatment options. Tumor mutation burden (TMB) has been known as a novel biomarker in various tumor types. However, there has been little study of the role of TMB-high in gastro-entero-pancreatic (GEP)-NETs. Methods: We analyzed 31 metastatic GEP-NET patients who were newly diagnosed between 2013 to 2022. Next-generation sequencing (NGS) including TMB analysis, as a routine clinical practice was performed. The TruSight Oncology 500 assay from Illumina was used as a cancer panel. Results: Among a total of 31 patients, the median TMB was 4.7 mutation/Mb (3.10-6.3). Primary origin was stomach in 4 (12.9%), small bowel in 2 (6.5%), rectum in 7 (22.6%), pancreas in 21 (38.7%), bile duct in 1 (3.2%), gall bladder in 4 (12.9%), liver in 1 (3.2%) patient. 17 (54.8%) patients were diagnosed with well-differentiated NET with grade 1 in 3 (9.7%), and grade 2 in 14 (45.2%) patients. Grade 3 NET (neuroendocrine carcinoma) was confirmed in 14 (45.2%) patients. The median number of metastases was 2.7 (1.0-4.0). The most common metastatic site was the liver (26 patients, 83.9%). All tumors were classified as type of micro-satellite stable (MSS). Only one patient had the tumor with high TMB (266.4 mutation/Mb). This tumor was classified as the grade 3 neuroendocrine carcinoma and the primary tumor site was pancreas. Conclusions: This analysis revealed that the GEP-NETs were generally considered as tumor-type of low TMB. However, uncommonly, GEP-NET with high-TMB could be found. For the precision medicine, the NGS test is needed as a routine clinical practice in this tumor type.

ODP300 c-MET expression in MEN1-associated neuroendocrine tumors

Abstract Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most common functional GEP-NETs in patients with MEN1. c-MET is a proto-oncogene that encodes for c-MET, a tyrosine kinase receptor which promotes tumor cell motility, proliferation, survival, invasion, and metastasis. Studies in patients with sporadic gastrinomas and pancreatic NETs (PNETs) have shown that c-MET expression correlates with decreased survival. While c-MET inhibitors are currently in various stages of investigation for treatment of carcinoids and sporadic PNETs, data regarding their efficacy in patients with MEN1-related GEP NETs is lacking. The majority of trials in patients with GEP-NETs exclude or do not report the number of patients with MEN1. Importantly, somatic MEN1 mutations are observed in 20-40% of sporadic NETs (gastrinomas, PNETs, lung NETs, etc.) but correlation of cMET expression with the presence of somatic or germline MEN1 mutations has not been reported. We sought to investigate the expression of c-MET in tumor tissue from germline MEN1 patients with metastatic GEP-NETs. Methods We identified subjects with a germline positive MEN1 mutation and pathologically confirmed distant metastasis who had a follow-up visit between 2018-2020. Of these, we selected subjects with available tissue specimens (including either multiple organ sources or different tumor types). Where available, we identified specimens from multiple source or tumor types. Immunohistochemistry (IHC) to detect c-MET was performed with anti-MET (Cell Signaling) using the DAKO IHC kit (Agilent). IHC slides were imaged and observed to score the level of c-MET staining (-, 1+ to 5+). A score of 3+ or higher was considered consistent with overexpression. We investigated if age at initial GEP-NET presentation, tumor type, tissue source, tumor grade, total number of surgeries for GEP-NET, number of sites of distant metastasis and disease status from overall GEP-NET burden over the preceding 12 months (stable/progressive) predicted c-MET expression. Results Eight subjects with available tissue specimens were identified, of which six had tissue from multiple organs while five had tissue from multiple tumor types. Six subjects (75%) showed increased expression of c-MET in one or more tumor specimen(s). The frequency of c-MET overexpression varied with tumor types – carcinoids (n=2/2; 100%), gastrinomas (n=3/5; 60%) and non-functional tumors (n=3/6; 50%). c-MET expression also varied among different tumors in the same patient. Tumor tissue from liver (n=2/2), duodenum (n=3/4), stomach (n=1/1), ovary (n=1/1), pancreas (n= 1/5), and lymph nodes (n=1/3), all showed over-expression of c-MET. No clear predictors of c-MET overexpression emerged. Conclusion Our finding suggests a role for c-MET expression in personalizing therapy for patients with MEN1-related NETs with distant metastases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.

68Ga]DOTATOC PET/CT Radiomics to Predict the Response in GEP-NETs Undergoing [177Lu]DOTATOC PRRT: The "Theragnomics" Concept.

Simple SummaryThe radiological response assessment of neuroendocrine tumors (NET) to peptide receptor radionuclide therapy (PRRT) using [177Lu]DOTATOC is still suboptimal due to the high variability in targeted somatostatin receptor 2 (SSTR-2) expression and histological heterogeneity among patients with well-differentiated NET. Promising and innovative laboratory assays have been proposed, but they are highly costly and not easily accessible. Machine learning offers new opportunities to provide quantitative characteristics from molecular images that cannot be appreciated by the human eye. We therefore retrospectively analyzed [68Ga]DOTATOC PET/CT images before and after complete [177Lu]DOTATOC PRRT in well-differentiated progressive, metastatic gastroenteropancreatic NET and obtained radiomics features as new and reliable imaging parameters that correlate to the response to PRRT and might be used for improved patient selection in the future.Despite impressive results, almost 30% of NET do not respond to PRRT and no well-established criteria are suitable to predict response. Therefore, we assessed the predictive value of radiomics [68Ga]DOTATOC PET/CT images pre-PRRT in metastatic GEP NET. We retrospectively analyzed the predictive value of radiomics in 324 SSTR-2-positive lesions from 38 metastatic GEP-NET patients (nine G1, 27 G2, and two G3) who underwent restaging [68Ga]DOTATOC PET/CT before complete PRRT with [177Lu]DOTATOC. Clinical, laboratory, and radiological follow-up data were collected for at least six months after the last cycle. Through LifeX, we extracted 65 PET features for each lesion. Grading, PRRT number of cycles, and cumulative activity, pre- and post-PRRT CgA values were also considered as additional clinical features. [68Ga]DOTATOC PET/CT follow-up with the same scanner for each patient determined the disease status (progression vs. response in terms of stability/reduction/disappearance) for each lesion. All features (PET and clinical) were also correlated with follow-up data in a per-site analysis (liver, lymph nodes, and bone), and for features significantly associated with response, the Δradiomics for each lesion was assessed on follow-up [68Ga]DOTATOC PET/CT performed until nine months post-PRRT. A statistical system based on the point-biserial correlation and logistic regression analysis was used for the reduction and selection of the features. Discriminant analysis was used, instead, to obtain the predictive model using the k-fold strategy to split data into training and validation sets. From the reduction and selection process, HISTO_Skewness and HISTO_Kurtosis were able to predict response with an area under the receiver operating characteristics curve (AUC ROC), sensitivity, and specificity of 0.745, 80.6%, 67.2% and 0.722, 61.2%, 75.9%, respectively. Moreover, a combination of three features (HISTO_Skewness; HISTO_Kurtosis, and Grading) did not improve the AUC significantly with 0.744. SUVmax, however, could not predict the response to PRRT (p = 0.49, AUC 0.523). The presented preliminary “theragnomics” model proved to be superior to conventional quantitative parameters to predict the response of GEP-NET lesions in patients treated with complete [177Lu]DOTATOC PRRT, regardless of the lesion site.

Application of FLIC model to predict adverse events onset in neuroendocrine tumors treated with PRRT

To develop predictive models of side effect occurrence in GEPNET treated with PRRT. Metastatic GEPNETs patients treated in our centre with PRRT (177Lu-Oxodotreotide) from 2019 to 2020 were considered. Haematological, liver and renal toxicities were collected and graded according to CTCAE v5. Patients were grouped according with ECOG-PS, number of metastatic sites, previous treatment lines and therapies received before PRRT. A FLIC model with backward selection was used to detect the most relevant predictors. A subsampling approach was implemented to assess variable selection stability and model performance. Sixty-seven patients (31 males, 36 females, mean age 63) treated with PRRT were considered and followed up for 30 weeks from the beginning of the therapy. They were treated with PRRT as third or further lines in 34.3% of cases. All the patients showed at least one G1–G2, meanwhile G3–G5 were rare events. No renal G3–G4 were reported. Line of PRRT administration, age, gender and ECOG-PS were the main predictors of haematological, liver and renal CTCAE. The model performance, expressed by AUC, was > 65% for anaemia, creatinine and eGFR. The application of FLIC model can be useful to improve GEPNET decision-making, allowing clinicians to identify the better therapeutic sequence to avoid PRRT-related adverse events, on the basis of patient characteristics and previous treatment lines.

Initiation of Somatostatin analogues for neuroendocrine tumor patients: a cost-effectiveness analysis

Background & AimsGastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous neoplasms. Although some have a relatively benign and indolent natural history, others can be aggressive and ultimately fatal. Somatostatin analogues (SSAs) improve both quality of life and survival for these patients once they develop metastatic disease. However, these drugs are costly and their cost-effectiveness is not known.MethodsA decision-analytic model was developed and analyzed to compare two treatment strategies for patients with Stage IV GEP-NETs. The first strategy had all patients start SSA immediately while the second strategy waited, reserving SSA initiation until the patient showed signs of progression. Sensitivity analysis was performed to explore model parameter uncertainty.ResultsOur model of patients age 60 with metastatic GEP-NETs suggests empiric initiation of SSA led to an increase 0.62 unadjusted life-years and incremental increase in quality-adjusted life years (QALYs) of 0.44. The incremental costs were $388,966 per QALY and not cost-effective at a willingness-to-pay threshold of $100,000. Death was attributed to GEP-NETs for 94.1% of patients in the SSA arm vs. 94.9% of patients in the DELAY SSA arm. Sensitivity analysis found that the model was most sensitive to costs of SSAs. Using probabilistic sensitivity analysis, the SSA strategy was only cost-effective 1.4% of the time at a WTP threshold of $100,000 per QALY.ConclusionsOur modeling study finds it is not cost-effective to initiate SSAs at time of presentation for patients with metastatic GEP-NETs. Further clinical studies are needed to identify the optimal timing to initiate these drugs.

Is SUVmax a useful marker for progression-free survival in patients with metastatic GEP-NET receiving 177Lu-DOTATATE therapy?

The prognostic potential of pretreatment maximum standardized uptake volume (SUVmax) on gallium-68-DOTATATE was evaluated with positron emission tomography/computed tomography (68Ga-DOTATATE PET/CT) in 37 patients with G1/G2 gastroenteropancreatic neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with lutetium-177-[DOTAo,Tyr3] octreotate (177Lu-DOTATATE) after the failure of somatostatin analogues. The mean and total SUVmax were used in 68Ga-DOTATATE PET/CT before 177Lu-DOTATATE treatment to assess the progression-free survival (PFS). The responses of the patients were evaluated as partial response in 8 (32%) patients, stable disease in 12 (48%), and progressive disease in 5 (20%). The median PFS was 18 months; longer than this threshold in 14 patients (26.0 months) and shorter in 11 (8.4 months). The mean SUVmax of metastases in the liver (34.15±17.89 vs. 14.69±9.17, P=0.004) and mean SUVmax of all body metastatic lesions (33.05±14.32 vs. 15.26±4.84, P=0.001) were higher in patientswith longer PFS. The tumor grade, the origin of the tumor, Ki67 status, and previous somatostatin treatment history were not significantly different between the two PFS groups. The pre-treatment SUVmax values of 68Ga-DOTATATE PET/CT in lesions are a potential prognostic factor for PFS in well-differentiated gastroenteropancreatic neuroendocrine tumors undergoing 177Lu-DOTATATE treatment, and could be a useful parameter for the treatment selection.

Safety of 177Lu-DOTATATE in patients with advanced neuroendocrine tumors: Data from a U.S. expanded access program.

4604 Background: The NETTER-1 clinical trial showed that peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE increased progression-free survival in patients with somatostatin-receptor-positive advanced midgut neuroendocrine tumors (NETs) compared with high-dose octreotide long-acting repeatable, and was associated with few serious adverse events (AEs). To assess the safety profile of 177Lu-DOTATATE in a real-world population, we analyzed safety data from a US expanded access program (NCT02705313). Methods: Patients had inoperable, histologically proven, somatostatin-receptor-positive, locally advanced or metastatic GEPNETs (Ki-67 index ≤ 20%) that progressed after somatostatin analog therapy. Exclusion criteria were: surgery, radiotherapy or chemotherapy in the last 12 weeks; treatment with an interferon, mTOR inhibitor, or other systemic therapy in the last 4 weeks; or ongoing octreotide therapy that could not be interrupted for PRRT. Patients with impaired renal function (serum creatinine &gt; 1.7 mg/dL or creatinine clearance &lt; 50 mL/min) or serious coexisting conditions were excluded. The analysis included patients who received ≥ 1 cycle of 177Lu-DOTATATE between July 5, 2016 and December 21, 2018. Data were collected from the first cycle to the latest data collection point (up to October 7, 2019). Results: 299 patients received a mean 177Lu-DOTATATE cumulative dose of 552 mCi (20.4 GBq) (standard deviation [SD]: 220 mCi [8.1 GBq]) over a mean of 2.8 cycles (SD: 1.1). Mean age was 60.8 years (SD: 11.7); 38.5% of patients were men. Over a mean follow-up of 131 days (SD: 87), 48.8% of patients reported treatment-related AEs (TRAEs), with a maximum severity of grade 1, 2 and 3 for 26.8% (n = 80), 18.1% (n = 54) and 4.0% (n = 12) of patients, respectively; there were no grade 4–5 TRAEs. The most common TRAEs of any grade (≥ 5.0% of patients) were nausea (31.1%), vomiting (13.7%), fatigue (9.4%) and thrombocytopenia (6.0%). The most prevalent grade 3 TRAEs were lymphocyte count decrease (1.0%) and thrombocytopenia (0.7%). Serious TRAEs occurred in 1.0% of patients (carcinoid crisis, dehydration, syncope and vomiting). AEs led to dose modification in 1.7% of patients, dose delay in 6.4% (most commonly due to nausea [2.0%] or thrombocytopenia [2.0%]) and discontinuation in 1.3% (due to thrombocytopenia [1.0%] and extravasation [0.3%]). Conclusions: In a real-world population of US patients with advanced GEPNETs, 177Lu-DOTATATE treatment was well tolerated with few TRAEs, consistent with the safety profile in the NETTER-1 trial. Clinical trial information: NCT02705313 .

Broadening horizons with 225Ac-DOTATATE targeted alpha therapy for gastroenteropancreatic neuroendocrine tumour patients stable or refractory to 177Lu-DOTATATE PRRT: first clinical experience on the efficacy and safety.

The objective of this study was to investigate and present the early results on the efficacy, safety, and quality of life of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with advanced, progressive, 177Lu-DOTATATE refractory, and somatostatin receptor (SSTR) expressing metastatic GEP-NETs. In this prospective study, we recruited patients with metastatic GEP-NETs who were stable or progressive disease on 177Lu-DOTATATE therapy. Systemic TAT using 225Ac-DOTATATE was performed in all the patients with 225Ac-DOTATATE (100kBq/kg body weight) at an interval of 8weeks. The primary end point was to assess the objective response (measured by RECIST 1.1 and functional M.D. Anderson criteria). The secondary end points included biochemical response assessment as per the Italian Trials in Medical Oncology (ITMO), adverse event profile as per CTCAE v5.0, and clinical response assessment by the quality of life (assessed with EORTC QLQ-GI.NET21 patient-based questionnaire). Between April 2018 and March 2019, 32 patients (17 females, 15 males, mean age 52 ± 9.2years, 35-72years) with either stable disease after completing 177Lu-DOTATATE therapy (14, 44%) or progressive disease on 177Lu-DOTATATE therapy (18, 56%) were included in the study. The morphological response was assessed in 24/32 patients that revealed partial remission in 15 and stable disease in 9. There was no documented disease progression or deaths in the median follow-up of 8months (range 2-13months). There was a significant decrease in the plasma chromogranin level post-225Ac-DOTATATE therapy (P < 0.0001). Our short-term clinical results indicate 225Ac-DOTATATE TAT as a promising treatment option which adds a new dimension in patients who are refractory to 177Lu-DOTATATE therapy or have reached the maximum prescribed cycles of 177Lu-DOTATATE therapy.

Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors.

4114 Background: Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs). Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D), safety data and early clinical efficacy in metastatic GEPNET patients was conducted. Methods: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 month. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had &gt; 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Conclusions: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429.

Patterns of Care Among Real-World Patients with Metastatic Neuroendocrine Tumors.

Although recent pivotal trials (PROMID, CLARINET) have established somatostatin analogs (SSAs) as first-line agents for neuroendocrine tumors (NETs), their use in clinical practice is largely unknown. We aimed to understand real-world management and treatment of gastroenteropancreatic (GEP) NETs. Patients with metastatic GEP-NETs treated with SSAs, lanreotide depot or octreotide long-acting release (LAR), between January 1, 2015, and December 31, 2015, were identified from a U.S. claims database supplemented with chart review for a subset of patients. Descriptive statistics summarized patients' demographics, clinical characteristics, treatment patterns, and healthcare resource use. Univariate and multivariate comparisons were made across SSA groups. Among 548 patients treated with an SSA for metastatic GEP-NET (lanreotide = 108; octreotide = 440), demographic and clinical characteristics were similar across groups, except more patients with pancreatic NETs were treated with lanreotide (38.7% vs. 6.3%, p < .01). More octreotide patients had a diagnosis of carcinoid syndrome compared with lanreotide patients (19.8% vs. 11.1%, p = .02). Approximately 1.1% of patients received lanreotide (>120 mg every 4 weeks [Q4W]) at a dose above label compared with 12.7% of octreotide patients (>30 mg Q4W; p < .01). At 1.5 years after SSA initiation, 85.7% (95% confidence interval, 74.3%-92.3%) were still on index SSA as reported by the physician. Variances between chart review and claims data were significant. SSAs were common in first-line systemic intervention, but dose escalations and dosing deviations outside of label were noted. Variances between claims and chart review warrant additional research to compare methodologies. With an increasing focus on value-based care in oncology, it is critical to understand the use of, and outcomes with, these agents in community practices. The aim of this study was to enhance understanding of real-world management and treatment of metastatic neuroendocrine tumors (NETs), with particular focus on systemic therapy with a somatostatin analog (SSA). As per published guidelines, SSAs are common in first-line systemic intervention, but dose escalations and dosing deviations outside of the label are noted for symptom control. Nevertheless, oncologists must weigh the implications of the use of above-label dosing of SSAs to manage and treat patients with metastatic NET within a value-based care framework.

Outcomes of locoregional treatment for unifocal progression in widespread metastatic gastroenteropancreatic neuroendocrine tumors.

472 Background: New systemic treatments have improved the therapeutic landscape for patients with progressive, metastatic GEP-NETs. While drugs such as everolimus are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE), or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy, and sparing them toxicities of a new systemic treatment. Methods: We reviewed records of patients treated at a large referral center to identify patients seen between 1/2014 and 5/2017 with metastatic GEP-NETs who underwent a local treatment for focal progression. Patients undergoing lobar HAE or cytoreductive hepatic surgery were not included. The primary endpoint was time to new systemic therapy. Secondary endpoints included time to any additional intervention (systemic or local), progression free survival, and side effects of treatment. Results: 59 patients were identified who underwent a form of local treatment for a progressive metastatic tumor in the setting of widespread metastases. 27% underwent resection, 29% RFA, 25% external beam radiation, and 19% selective HAE. With a median follow-up of 17 months, 19 patients (32.2%) eventually progressed to the extent that they received salvage systemic treatment. 6 patients (10.2%) progressed and received further local treatment. Median time to new systemic treatment was 42 months (95% CI, 9.7-74.3 months). Median time to any additional intervention was 21 months (95% CI, 11.4-30.6 months). 4 patients died, all of whom had progressed and received further systemic treatment. Conclusions: We identified a large cohort of patients with metastatic GEP-NETs who underwent a local treatment for unifocal progression in the setting of widespread metastases. Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.

Metastatic gastroenteropancreatic neuroendocrine tumors treated with somatostatin analogues: Ten years experience in a third level hospital in Mexico City.

514 Background: Gastroenteropancreatic neuroendocrine tumors (GEP NET´s) are infrequent tumors, with a variety of symptoms depending of the kind of peptide they secrete as well as the affected organs. Long acting somatostatin analogues have shown an adequate rate of symptom control in functional tumors, they also have demonstrated antiproliferative effect, which is translated in a significant improvement of progression free and overall survival Methods: In this retrospective analysis of patients with metastatic GEP NET treated with long acting somatostatin analogues as first line, treated between 2005 and 2015, we evaluated clinical and pathological features, symptoms, disease control and survival adjusted with OMS classification Results: Our cohort included 95 patients with a mean age of 53 years. Primary affected sites were midgut (29.4%), followed by pNET (17.%), stomach (14.7%), and primary unknown in 14%. 20% of cases were functional tumors with diarrhea as the most common symptom in 70% and flushing in 50%. Considering the whole cohort the most prevalent symptom was abdominal pain in the 50% of cases. The OMS classification showed low grade tumors in 65% and 35% intermediate grade. Most common metastatic organ sites were; liver only 35%, liver and other 30%, peritoneum 10% and lymph nodes in 6%, non-specified sites in 19%. Somatostatine analogues used in first line were octreotide in 80% and lanreotide in 20%. Survival results demonstrated a progression free survival for the whole cohort of 84months. No differences between lanreotide and octreotide were observed. Conclusions: This study represents the first Mexican cohort of patients with GEP NET’s treated with somatostatin analogues with a long follow up.

Lanreotide reduces hospital costs for metastatic GEP-NETs

Lanreotide reduces hospital costs for metastatic GEP-NETs

PD-009 - Overall survival in patients diagnosed with metastatic GEP-NET in Sweden

PD-009 - Overall survival in patients diagnosed with metastatic GEP-NET in Sweden

P-177 - Efficасу of long-acting somatostatin analogues (SA) in patients (pts) with highly differentiated gastroenteropancreatic neuroendocrine tumors (GEP NETs)

Introduction: Antiproliferative efficacy of SA in midgut NETs was proved in PROMID study. But this study included patients only with G1 tumors. We assessed efficacy of the SA in pts with metastatic (advanced) G1 and G2 GEP NETs, and also in patients previously treated with chemotherapy. Methods: 60 pts with morphologically proven GEP NETs; among them 18 male (30%) and 42 female (70%), 18 to 82 years old (mean age - 55 years). 28 (47%) pts were previously untreated and 32 (53%) pts had received prior chemotherapy. Primary tumor site: pancreas -19 (32%), intestine -21 (35%), the unknown primary site -20 (33%) cases. Metastases sites: liver -52 (87%), spleen -2 (3%), peritoneum - 13 (22%), lymph nodes - 24 (40%), lungs - 6 (10%), bones - 8 (13%). In all cases with unknown primary site patients had liver metastases. Pathomorphology: G1 - 22 (37%) pts, G2 - 27 (45%) pts and 11 (18%) pts had only cytological verification. Carcinoid syndrome and increased chromogranin A and serotonin serum levels and 5-HIAA urine level were reported in 52 (87%) pts. Regimens: 45 (70%) pts received only SA in the dose of 30 or 40 mg/m2 every 28 days, 13 (30%) pts were given SA in the dose of 30 or 40 mg in combination with interferon α. Results: 51 (85%) pts had stable disease (SD), 9 (15%) pts progressed (PD). Reduction and normalization of CgA, serotonin or 5 - HIAA levels were achieved in 48 (80%) pts. Symptoms control was observed in all cases. Median progression-free survival was 40 months. Median overall survival has not been reached yet. Conclusion: The long-acting somatostatin analogues are effective drugs for the treatment of highly differentiated GEP NETs.