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 progressionfree 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.)

Background Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. Methods We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. Results The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). Conclusions Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.

Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

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Summary Background Effective systemic therapies for patients with progressive neuroendocrine tumours of lung or gastrointestinal tract are limited. We aimed to assess the efficacy and safety of everolimus in this patient population. Methods In RADIANT-4, a randomised, double-blind, placebo-controlled, phase 3 study, patients with advanced, progressive, well-differentiated, nonfunctional lung or gastrointestinal neuroendocrine tumours were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomised in a 2:1 ratio to everolimus 10 mg/day or placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and prior somatostatin analogue treatment. The primary endpoint was progression-free survival assessed by central radiology review. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Findings From April 2012 to August 2013, a total of 302 patients were enrolled, of whom, 205 were allocated to everolimus 10 mg/day and 97 to placebo. Median progression-free survival was 11.0 months (95% confidence interval [CI], 9.2–13.3) in the everolimus arm and 3.9 months (95% CI, 3.6–7.4) in the placebo arm. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR], 0.48; 95% CI, 0.35–0.67; p<0.00001). Although statistically not significant, a trend towards improved survival was observed in the first pre-planned interim overall survival analysis (HR, 0.64; 95% CI: 0.40, 1.05; one-sided p=0.037; boundary for statistical significance, 0.0002). Grade 3 or 4 drug-related adverse events (everolimus vs placebo) were relatively infrequent and included stomatitis (9% vs 0), diarrhoea (7% vs 2%), infections (7% vs 0), anaemia (4% vs 1%), fatigue (4% vs 1%), and hyperglycaemia (4% vs 0). Interpretation Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side effect profile of everolimus.

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PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.