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 (P177Lu-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.)
Document Type
Article
Publication Date
1-12-2017
Digital Object Identifier (DOI)
https://doi.org/10.1056/NEJMoa1607427
Related Content
A complete list of investigators in the Neuroendocrine Tumors Therapy (NETTER-1) trial is provided in the Supplementary Appendix, available at NEJM.org.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Repository Citation
Strosberg, Jonathan; El-Haddad, Ghassan; Wolin, Edward M.; Hendifar, Andrew; Yao, James; Chasen, Beth; Mittra, Erik; Kunz, Pamela L.; Kulke, Matthew H.; Jacene, Heather; Bushnell, David; O’Dorisio, Thomas M.; Baum, Richard P.; Kulkarni, Harshad R.; Caplin, Martyn; Lebtahi, Rachida; Hobday, Timothy; Delpassand, Ebrahim; Van Cutsem, Eric; Benson, Al; Srirajaskanthan, Rajaventhan; Pavel, Marianne; Mora, Jaime; Berlin, Jordan; Grande, Enrique; Reed, Nicholas; Seregni, Ettore; Öberg, Kjell; Sierra, Maribel Lopera; and Santoro, Paola, "Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors" (2017). Markey Cancer Center Faculty Publications. 98.
https://uknowledge.uky.edu/markey_facpub/98
Protocol
nejmoa1607427_appendix.pdf (343 kB)
Supplementary Appendix
nejmoa1607427_disclosures.pdf (474 kB)
Disclosure Forms
Notes/Citation Information
Published in The New England Journal of Medicine, v. 376, no. 2, p. 125-135.
From The New England Journal of Medicine, Jonathan Strosberg,Ghassan El-Haddad, Edward Wolin, Andrew Hendifar, James Yao, Beth Chasen, Erik Mittra, Pamela L. Kunz, Matthew H. Kulke, Heather Jacene, David Bushnell, Thomas M. O’Dorisio, Richard P. Baum, Harshad R. Kulkarni, Martyn Caplin, Rachida Lebtahi, Timothy Hobday, Ebrahim Delpassand, Eric Van Cutsem, Al Benson, Rajaventhan Srirajaskanthan, Marianne Pavel, Jaime Mora, Jordan Berlin, Enrique Grande, Nicholas Reed, Ettore Seregni, Kjell Öberg, Maribel Lopera Sierra, Paola Santoro, Thomas Thevenet, Jack L. Erion, Philippe Ruszniewski, Dik Kwekkeboom, and Eric Krenning, Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors, 376, 125-135. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission.
Due to the large number of authors, only the first 30 and the authors affiliated with the University of Kentucky are listed in the author section above. For the complete list of authors, please download this article or visit: https://doi.org/10.1056/NEJMoa1607427