Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Efficacy and Toxicity Analysis of mFOLFIRINOX in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

BACKGROUND: High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs. PATIENTS AND METHODS: We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX. RESULTS: A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities. CONCLUSIONS: mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.

EGFR is a potential therapeutic target for highly glycosylated and aggressive pancreatic neuroendocrine neoplasms.

pNENs are relative indolent tumors with heterogeneous clinical presentation at diagnosis. It is important to establish aggressive subgroups of pNENs and identify potential therapeutic targets. Patients with pNEN (322 cases) were included to examine the association between glycosylation biomarkers and clinical/pathological traits. The molecular and metabolic features stratified by glycosylation status were assessed by RNA-seq/whole exome sequencing and immunohistochemistry. A considerable proportion of patients had elevated glycosylation biomarkers (carbohydrate antigen [CA] 19-9, 11.9%; CA125, 7.5%; carcinoembryonic antigen [CEA], 12.8%). CA19-9 (hazard ratio [HR] = 2.26, P = .019), CA125 (HR = 3.79, P = .004) and CEA (HR = 3.16, P = .002) were each independent prognostic variables for overall survival. High glycosylation group, defined as pNENs with elevated level of circulating CA19-9, CA125 or CEA, accounted for 23.4% of all pNENs. High glycosylation (HR = 3.14, P = .001) was an independent prognostic variable for overall survival and correlated with G3 grade (P < .001), poor differentiation (P = .001), perineural invasion (P = .004) and distant metastasis (P < .001). Epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival (P = .020). A clinical trial focusing on EGFR expressed pNENs was initiated (NCT05316480). Thus, pNEN with aberrant glycosylation correlates with a dismal outcome and suggests potential therapeutic target of EGFR.

RNA Expression-based Analysis to Predict Response in Patients with Metastatic Mismatch Repair Proficient Colorectal Cancer Treated with Regorafenib and Nivolumab.

Introduction We previously conducted a phase I/Ib study (NCT03712943) with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the role of Xerna™ TME Panel in predicting the treatment response. Methods 22 archival pretreatment tumor samples were subjected to the Xerna™ TME Panel, a machine learning-based RNA-sequencing biomarker assay. The Xerna TME subtypes were evaluated for correlation with overall survival (OS), progression free survival (PFS), disease control rate (DCR), and other biomarkers including KRAS, PD-L1, CD8 expression, and Treg cells in tumor microenvironment. Results Based on Xerna™ TME Panel, four patients with immune active (IA) subtype and six patients with immune suppressed (IS) subtype were classified as biomarker-positive, and five with angiogenic (A) subtype and seven with immune desert (ID) subtype were biomarker-negative. While not reaching statistical significance, Xerna TME biomarker-positive patients seemed to have longer median PFS (7.9 vs. 4.1 months, P=0.254), median OS (15.75 vs. 11.9 months, P=0.378), and higher DCR (70% vs. 58%, P=0.675). The IA subtype in our cohort had higher levels of CD4+ FOXP3+ Treg cells, whereas the A subtype showed lower levels of Treg cells. Conclusion Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab might be of value for predictive clinical benefit. Further studies are needed to evaluate the predictive role of Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC.

Belzutifan in a Patient With VHL-Associated Metastatic Pancreatic Neuroendocrine Tumor.

von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease characterized by mutation of the VHL gene. This gene encodes for the VHL protein, which regulates the activity of HIF-α, a transcription factor involved in the cellular response to hypoxia. Mutations in VHL lead to the accumulation of HIF-α and, consequently, the engagement of hypoxia-sensitive genes with tumorigenic effects. VHL disease is associated with the development of tumors in multiple organs, including pancreatic neuroendocrine tumors (pNETs). Belzutifan is an HIF-α inhibitor; however, it has not been previously evaluated in patients with metastatic or treatment-refractory pNETs. This report presents a 43-year-old woman with VHL-associated metastatic pNET treated with belzutifan after progression on multiple systemic therapies. She began treatment with belzutifan and experienced partial radiographic response within 1 month of treatment. Other than asymptomatic anemia, no adverse effects developed during 5 months of ongoing therapy. Belzutifan is an inhibitor of HIF-2α that targets the underlying pathophysiology of VHL-associated pNETs. Our case report describes exceptional activity in a metastatic pNET arising from VHL.

177Lu-Dotatate plus long-acting octreotide versus high­dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results. METHODS: This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. FINDINGS: From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the 177Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the 177Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up. INTERPRETATION: 177Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up. FUNDING: Advanced Accelerator Applications, a Novartis company.

Relationship between metabolic toxicity and efficacy of everolimus in patients with neuroendocrine tumors: A pooled analysis from the randomized, phase 3 RADIANT-3 and RADIANT-4 trials.

BACKGROUND: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors such as everolimus. This post hoc pooled analysis assessed the potential impact of these events on the efficacy of everolimus. METHODS: Patients with advanced, low- or intermediate-grade pancreatic, gastrointestinal, or lung neuroendocrine tumors received either oral everolimus at 10 mg/d or a placebo in the RAD001 in Advanced Neuroendocrine Tumors 3 (RADIANT-3) and RAD001 in Advanced Neuroendocrine Tumors 4 (RADIANT-4) trials. A landmark progression-free survival (PFS) analysis by central review was performed for patients treated for at least 16 weeks (n = 308) and according to the occurrence of any-grade adverse events (AEs) within this treatment period. RESULTS: The overall PFS with everolimus from the pooled analysis was 11.4 months (95% confidence interval, 11.01-13.93 months), which was consistent with the findings of RADIANT-3 and RADIANT-4. Overall, 19.1% and 9.8% of patients in RADIANT-3 and 11.9% and 6.4% of patients in RADIANT-4 developed any-grade hyperglycemia and hypercholesterolemia, respectively (regardless of the study drug). The duration of everolimus exposure was longer in patients who developed these AEs versus patients without these AEs. Overall, 308 patients were exposed to treatment for at least 16 weeks (hyperglycemia, 39 of 269 patients; hypercholesterolemia, 20 of 288 patients). No association was observed between the development of these AEs and PFS (18.8 and 14.1 months with and without hyperglycemia, respectively, and 14.1 and 14.8 months with and without hypercholesterolemia, respectively). CONCLUSIONS: Although limitations apply because of the small number of AEs observed, there was no significant impact of these AEs on PFS; this suggests similar efficacy in the presence or absence of these events.

A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort.

BACKGROUND: The authors previously reported the results of the nonpancreatic neuroendocrine neoplasm cohort of the SWOG S1609 DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial, which permitted all histologic grades and had a 44% overall response rate (ORR) among patients with high-grade disease. Here they sought to validate their findings in a dedicated prospective cohort of high-grade neuroendocrine neoplasms within S1609. METHODS: A prospective, open-label, multicenter, phase 2 clinical trial of ipilimumab plus nivolumab was conducted across multiple rare tumor cohorts. The dedicated, high-grade neuroendocrine neoplasm cohort was examined here. The primary end point was the ORR according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Nineteen patients with high-grade neuroendocrine neoplasms (defined by local pathology review) were enrolled in this cohort of S1609. The most common primary sites were unknown primaries (21%), which were followed by the rectum, gastroesophageal junction, cervix, and pancreas (11%). The median number of lines of prior therapy was 1 (range, 0-3). All patients were microsatellite-stable. The median Ki-67 value was 80%. The ORR was 26% (95% confidence interval [CI], 11%-45%), and the clinical benefit rate (stable disease for ≥6 months plus partial responses plus complete responses) was 32% (95% CI, 13%-57%). The 6-month PFS rate was 32% (95% CI, 16%-61%) with a median PFS of 2.0 months (95% CI, 1.8 months to ∞) and a median OS of 8.7 months (95% CI, 6.1 months to ∞). The most common toxicities were fatigue (32%) and rash (26%), and the most common grade 3/4 immune-related adverse event was rash (15%); there were no events that required treatment discontinuation and no grade 5 events. CONCLUSIONS: Ipilimumab plus nivolumab demonstrated a 26% ORR in patients with high-grade neuroendocrine neoplasms, with durable responses seen in patients with refractory disease.

A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer.

BACKGROUND: MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC. METHODS: This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively. CONCLUSION: Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC. CLINICALTRIALS. GOV IDENTIFIER: NCT03332498.

Efficacy of FOLFOX in Patients with Aggressive Pancreatic Neuroendocrine Tumors After Prior Capecitabine/Temozolomide.

BACKGROUND: 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) has activity in pancreatic neuroendocrine tumors (pNETs), but its use is limited, partly because of toxicities. pNETs can often become aggressive over time. We evaluated the efficacy of FOLFOX in patients with aggressive pNETs who had progressed after capecitabine plus temozolomide (cap/tem) among other treatments. MATERIALS AND METHODS: This was a retrospective study of all patients with well-differentiated metastatic pNETs, treated at an academic cancer center between January 2008 and June 2019, who received FOLFOX and had received cap/tem in the past. The primary endpoint was objective response rate. RESULTS: Thirty-one patients met eligibility criteria. Twenty-five received FOLFOX, and six received FOLFOX with bevacizumab. Patients were heavily pretreated, having received a median of three prior lines of systemic therapy prior to FOLFOX (range, 1-8). Three (9.7%) patients had grade [G]1 tumors, 16 (51.6%) had G2, and 6 (19.4%) had G3, and grade was unspecified in 6 (19.4%) patients. Fourteen (45.2%) exhibited a best response of partial radiographic response per RECIST 1.1 criteria, 15 (48.4%) stable disease, and 2 (6.4%) progressive disease; overall response rate was 45.2% and disease control rate was 93.5%. Median progression-free survival was 6 months (95% confidence interval [CI], 5.0-7.0), and median overall survival was 16 months from onset of study treatment (95% CI, 11.3-20.7) and 67 months from date of diagnosis (95% CI, 49.8-84.2). Median duration of treatment was 3 months, and median duration of response was 2 months. Toxicity profile was consistent with known adverse events associated with this regimen. CONCLUSION: FOLFOX is active in aggressive, heavily pretreated pNETs that have progressed on prior cap/tem chemotherapy; response durations are relatively short. IMPLICATIONS FOR PRACTICE: FOLFOX chemotherapy has robust activity in patients with rapidly progressive, heavily pretreated pancreatic neuroendocrine tumors (NETs), a setting in which few, if any, other options are likely to be effective. Durations of response, however, are relatively short, and new treatments are urgently needed for patients with aggressive transformation of pancreatic NETs.

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

BACKGROUND: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. MATERIALS AND METHODS: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014-2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. RESULTS: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6-173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6-16.2) and 11.9 months (95% CI, 8.6-14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2-16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1-4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8-86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2-10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. CONCLUSION: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. IMPLICATIONS FOR PRACTICE: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms.

PURPOSE: There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the ß-particle emitting radionuclide 177Lu ([177Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [225Ac]Ac-DOTA-TATE in patients that were refractory to [177Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [225Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). METHODS: [225Ac]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor-bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [225Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. RESULTS: [225Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 °C. All animals in the toxicity study appeared healthy 5 months post injection with no indications of toxicity, except that animals that received ≥111 kBq of [225Ac]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [225Ac]Ac-DOTA-TATE relative to controls. CONCLUSIONS: These results suggest significant potential for the clinical translation of [225Ac]Ac-DOTA-TATE for lung NENs.

Sensitivity and Specificity of the NETest: A Validation Study.

BACKGROUND: Secretory tumor markers traditionally measured in patients with neuroendocrine tumors (NET) are lacking sensitivity and specificity, and consequently they are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population of metastatic well-differentiated NETs of gastroenteropancreatic and lung origin and to evaluate NETest specificity in a mixed population of metastatic non-NET gastrointestinal (GI) malignancies and healthy individuals. DESIGN AND METHODS: Forty-nine patients with metastatic NETs, 21 patients with other metastatic GI cancers, and 26 healthy individuals were enrolled in the study. Samples were sent in a blinded fashion to a central laboratory, and an NETest value of 0-13% was considered normal. RESULTS: Using 13% as the upper limit of normal, the sensitivity of the NETest was 98% (95% CI 89-100%). The overall specificity was 66% (95% CI 51-79%), with 16 false-positive results. Specificity was 81% (95% CI 62-92%) among 26 healthy individuals and 48% (95% CI 26-70%) among patients with other GI malignancies. Using an updated normal range of 0-20%, sensitivity was unchanged, but specificity improved to 100% among healthy participants and to 67% among patients with other cancers. CONCLUSIONS: The sensitivity of the NETest is exceptionally high (>95%) in a population of metastatic, well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20% but relatively low when evaluating patients with other GI malignancies.

Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms.

BACKGROUND: The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors. METHODS: We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM. RESULTS: A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed. CONCLUSIONS: The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

An Update on the Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH).

OPINION STATEMENT: DIPNECH is caused by an idiopathic proliferation of pulmonary neuroendocrine cells which can lead to bronchiolitis and multifocal lung neuroendocrine tumors. Patients often present with chronic cough and dyspnea. Larger NETs may develop malignant potential. Somatostatin analogs can palliate chronic symptoms, particularly cough. Surgical resection can be considered for relatively large (e.g. >1 cm), progressive tumors.

Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials.

BACKGROUND: Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs. METHODS: Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint. RESULTS: Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related. CONCLUSIONS: Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered. CLINICAL TRIAL REGISTRATION NUMBER: NCT02939651 (10/20/2016).

Capecitabine and Temozolomide in Advanced Lung Neuroendocrine Neoplasms.

BACKGROUND: Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently showed significant activity in patients with pancreatic neuroendocrine tumors (NETs), but data in lung NETs are limited. METHODS: We retrospectively reviewed the records of patients treated at a large referral center to identify patients seen between January 2008 and September 2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Patients with small cell lung cancer were excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression-free survival, overall survival, and toxicity. RESULTS: Twenty patients were identified who received treatment with capecitabine and temozolomide. Fourteen (70%) had typical lung NETs, five had (25%) atypical carcinoids, and one (5%) had disease defined as a large-cell neuroendocrine carcinoma. Nineteen patients were evaluable for response. Six (30%) patients exhibited a best response of partial response per RECIST 1.1 criteria, 11 (55%) stable disease, and 2 (10%) progressive disease; objective response rate was 30%, and disease control rate was 85%. Eleven patients eventually progressed, only six of whom exhibited progression per RECIST 1.1 criteria. Median progression-free survival was 13 months (95% confidence interval [CI], 4.4-21.6 months). Median overall survival was 68 months (95% CI, 35.3-100.7 months). Toxicity profile was mild with mainly grade 1, expected toxicities. Six patients required dose reduction because of toxicity. CONCLUSION: The CAPTEM regimen is associated with a high response rate and a relatively tolerable toxicity profile in lung NENs. This regimen warrants further exploration in a prospective clinical trial. IMPLICATIONS FOR PRACTICE: Patients with advanced lung neuroendocrine neoplasms have very few systemic treatment options. The capecitabine and temozolomide regimen has previously shown significant activity in patients with pancreatic neuroendocrine tumors (NETs) but has not been explored in metastatic lung NETs. This study showed that this regimen is associated with a high response rate (30%) and a relatively tolerable toxicity profile in this population.

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors.

BACKGROUND: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS: Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).