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N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427.

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

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From the Moffitt Cancer Center, Tampa, FL (J.S., G.E.-H.); Markey Cancer Center, University of Kentucky, Lexington (E.W.); Cedars Sinai Medical Center, Los Angeles (A.H.), and Stanford University School of Medicine, Stanford (E.M., P.L.K.) - both in California; University of Texas M.D. Anderson Cancer Center (J.Y., B.C.) and Excel Diagnostics Imaging Clinic (E.D.), Houston; Dana-Farber Cancer Institute, Boston (M.H.K., H.J.); University of Iowa, Iowa City (D.B., T.M.O.); Zentralklinik, Bad Berka (R.P.B., H.R.K.), and Charité-Universitätsmedizin, Berlin (M.P.) - both in Germany; Royal Free Hospital (M.C.) and King's College Hospital NHS Foundation Trust (R.S.), London, and Beatson Oncology Centre, Glasgow (N.R.) - all in the United Kingdom; Hôpital Beaujon, Clichy (R.L., P.R.), and Advanced Accelerator Applications, St. Genis-Pouilly (T.T.) - both in France; Mayo Clinic College of Medicine, Rochester, MN (T.H.); University Hospitals and KU Leuven, Leuven, Belgium (E.V.C.); Robert H. Lurie Comprehensive Cancer Center, Chicago (A.B.); Hospital Universitari de Bellvitge, Barcelona (J.M.), and Hospital Universitario Ramón y Cajal, Madrid (E.G.) - both in Spain; Vanderbilt University Medical Center, Nashville (J.B.); Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan (E.S.); University Hospital, Uppsala University, Uppsala, Sweden (K.O.); Advanced Accelerator Applications USA, New York (M.L.S., P.S., J.L.E.); and Erasmus Medical Center, Rotterdam, the Netherlands (D.K., E.K.).



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.


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.


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.


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 number, NCT01578239 ; EudraCT number 2011-005049-11 .).

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