Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors

J. Strosberg*, G. El-Haddad, E. Wolin, A. Hendifar, J. Yao, B. Chasen, E. Mittra, P. L. Kunz, M. H. Kulke, H. Jacene, D. Bushnell, T. M. O'Dorisio, R. P. Baum, H. R. Kulkarni, M. Caplin, R. Lebtahi, T. Hobday, E. Delpassand, E. Van Cutsem, A. Benson & 15 others R. Srirajaskanthan, M. Pavel, J. Mora, J. Berlin, E. Grande, N. Reed, E. Seregni, K. Öberg, M. Lopera Sierra, P. Santoro, T. Thevenet, J. L. Erion, P. Ruszniewski, D. Kwekkeboom, E. Krenning

*Corresponding author for this work

Research output: Contribution to journalArticle

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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 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.).

Original languageEnglish (US)
Pages (from-to)125-135
Number of pages11
JournalNew England Journal of Medicine
Volume376
Issue number2
DOIs
StatePublished - Jan 12 2017

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Neuroendocrine Tumors
Octreotide
Survival Analysis
Control Groups
Disease-Free Survival
Lutetium
Confidence Intervals
Safety
Somatostatin Receptors
Lymphopenia
Survival
Poisons
Somatostatin
Neutropenia
Intravenous Infusions
Disease Progression
Therapeutics
Survival Rate
Randomized Controlled Trials
Kidney

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Strosberg, J., El-Haddad, G., Wolin, E., Hendifar, A., Yao, J., Chasen, B., ... Krenning, E. (2017). Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. New England Journal of Medicine, 376(2), 125-135. https://doi.org/10.1056/NEJMoa1607427
Strosberg, J. ; El-Haddad, G. ; Wolin, E. ; Hendifar, A. ; Yao, J. ; Chasen, B. ; Mittra, E. ; Kunz, P. L. ; Kulke, M. H. ; Jacene, H. ; Bushnell, D. ; O'Dorisio, T. M. ; Baum, R. P. ; Kulkarni, H. R. ; 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. ; Sierra, M. Lopera ; Santoro, P. ; Thevenet, T. ; Erion, J. L. ; Ruszniewski, P. ; Kwekkeboom, D. ; Krenning, E. / Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 2. pp. 125-135.
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title = "Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors",
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 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.).",
author = "J. Strosberg and G. El-Haddad and E. Wolin and A. Hendifar and J. Yao and B. Chasen and E. Mittra and Kunz, {P. L.} and Kulke, {M. H.} and H. Jacene and D. Bushnell and O'Dorisio, {T. M.} and Baum, {R. P.} and Kulkarni, {H. R.} and M. Caplin and R. Lebtahi and T. Hobday and E. Delpassand and {Van Cutsem}, E. and A. Benson and R. Srirajaskanthan and M. Pavel and J. Mora and J. Berlin and E. Grande and N. Reed and E. Seregni and K. {\"O}berg and Sierra, {M. Lopera} and P. Santoro and T. Thevenet and Erion, {J. L.} and P. Ruszniewski and D. Kwekkeboom and E. Krenning",
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language = "English (US)",
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pages = "125--135",
journal = "New England Journal of Medicine",
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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, Sierra, ML, Santoro, P, Thevenet, T, Erion, JL, Ruszniewski, P, Kwekkeboom, D & Krenning, E 2017, 'Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors', New England Journal of Medicine, vol. 376, no. 2, pp. 125-135. https://doi.org/10.1056/NEJMoa1607427

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, P. L.; Kulke, M. H.; Jacene, H.; Bushnell, D.; O'Dorisio, T. M.; Baum, R. P.; Kulkarni, H. R.; 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.; Sierra, M. Lopera; Santoro, P.; Thevenet, T.; Erion, J. L.; Ruszniewski, P.; Kwekkeboom, D.; Krenning, E.

In: New England Journal of Medicine, Vol. 376, No. 2, 12.01.2017, p. 125-135.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors

AU - Strosberg, J.

AU - El-Haddad, G.

AU - Wolin, E.

AU - Hendifar, A.

AU - Yao, J.

AU - Chasen, B.

AU - Mittra, E.

AU - Kunz, P. L.

AU - Kulke, M. H.

AU - Jacene, H.

AU - Bushnell, D.

AU - O'Dorisio, T. M.

AU - Baum, R. P.

AU - Kulkarni, H. R.

AU - Caplin, M.

AU - Lebtahi, R.

AU - Hobday, T.

AU - Delpassand, E.

AU - Van Cutsem, E.

AU - Benson, A.

AU - Srirajaskanthan, R.

AU - Pavel, M.

AU - Mora, J.

AU - Berlin, J.

AU - Grande, E.

AU - Reed, N.

AU - Seregni, E.

AU - Öberg, K.

AU - Sierra, M. Lopera

AU - Santoro, P.

AU - Thevenet, T.

AU - Erion, J. L.

AU - Ruszniewski, P.

AU - Kwekkeboom, D.

AU - Krenning, E.

PY - 2017/1/12

Y1 - 2017/1/12

N2 - 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.).

AB - 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.).

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U2 - 10.1056/NEJMoa1607427

DO - 10.1056/NEJMoa1607427

M3 - Article

VL - 376

SP - 125

EP - 135

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 2

ER -

Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. New England Journal of Medicine. 2017 Jan 12;376(2):125-135. https://doi.org/10.1056/NEJMoa1607427