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 .

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors / Strosberg, J; El Haddad, G; Wolin, E; Hendifar, A; Yao, J; Chasen, B; Mittra, E; Kunz, Pl; Kulke, Mh; Jacene, H; Bushnell, D; O'Dorisio, Tm; Baum, Rp; Kulkarni, Hr; Caplin, M; Lebtahi, R; Hobday, T; Delpassand, E; Van Cutsem, E; Benson, A; Srirajaskanthan, R; Pavel, M; Mora, J; Berlin, J; Grande, E; Reed, N; Seregni, E; Öberg, K; Lopera Sierra, M; Santoro, P; Thevenet, T; Erion, Jl; Ruszniewski, P; Kwekkeboom, D; Krenning, E; Van Cutsem, E; Ansquer, C; Baudin, E; Courbon, F; Giammarile, F; Ruszniewski, P; Taieb, D; Baum, Rp; Pavel, M; Scheidhauer, K; Weber, M; Bodei, L; Brianzoni, E; DELLE FAVE, Gianfranco; Chiara Grana, M; Mariani, G; Rindi, G; Seregni, E; Severi, S; Azevedo, I; Grande, E; Mora, J; Öberg, K; Sundin, A; Al‐nahhas, A; Caplin, M; Freemantle, N; Grossman, A; Manoharan, P; Reed, N; Srirajaskanthan, R; Anthony, L; Benson, Ab; Berlin, J; Bushnell, D; Delpassand, E; Garbus, S; Hendifar, A; Hobday, T; Kulke, M; Kvols, L; Metz, D; Mittra, E; Morse, M; Schipper, M; Strosberg, J; Wolin, E; Yao, J.. - In: THE NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - STAMPA. - 376:2(2017), pp. 125-135. [10.1056/NEJMoa1607427]

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

DELLE FAVE, Gianfranco;
2017

Abstract

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 .
2017
receptor radionuclide therapy; radiolabeled somatostatin analog; carcinoid-syndrome; prognostic-factors; survival; prrt; lu-177-dota-octreotate; lu-177-octreotate; scintigraphy; octreotide
01 Pubblicazione su rivista::01a Articolo in rivista
Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors / Strosberg, J; El Haddad, G; Wolin, E; Hendifar, A; Yao, J; Chasen, B; Mittra, E; Kunz, Pl; Kulke, Mh; Jacene, H; Bushnell, D; O'Dorisio, Tm; Baum, Rp; Kulkarni, Hr; Caplin, M; Lebtahi, R; Hobday, T; Delpassand, E; Van Cutsem, E; Benson, A; Srirajaskanthan, R; Pavel, M; Mora, J; Berlin, J; Grande, E; Reed, N; Seregni, E; Öberg, K; Lopera Sierra, M; Santoro, P; Thevenet, T; Erion, Jl; Ruszniewski, P; Kwekkeboom, D; Krenning, E; Van Cutsem, E; Ansquer, C; Baudin, E; Courbon, F; Giammarile, F; Ruszniewski, P; Taieb, D; Baum, Rp; Pavel, M; Scheidhauer, K; Weber, M; Bodei, L; Brianzoni, E; DELLE FAVE, Gianfranco; Chiara Grana, M; Mariani, G; Rindi, G; Seregni, E; Severi, S; Azevedo, I; Grande, E; Mora, J; Öberg, K; Sundin, A; Al‐nahhas, A; Caplin, M; Freemantle, N; Grossman, A; Manoharan, P; Reed, N; Srirajaskanthan, R; Anthony, L; Benson, Ab; Berlin, J; Bushnell, D; Delpassand, E; Garbus, S; Hendifar, A; Hobday, T; Kulke, M; Kvols, L; Metz, D; Mittra, E; Morse, M; Schipper, M; Strosberg, J; Wolin, E; Yao, J.. - In: THE NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - STAMPA. - 376:2(2017), pp. 125-135. [10.1056/NEJMoa1607427]
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