A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial

M. H. Kulke, P. Ruszniewski, E. Van Cutsem, C. Lombard-Bohas, J. W. Valle, W. W. De Herder, M. Pavel, E. Degtyarev, J. C. Brase, L. Bubuteishvili-Pacaud, M. Voi, R. Salazar, I. Borbath, N. Fazio, D. Smith, J. Capdevila, R. P. Riechelmann, J. C. Yao

Research output: Contribution to journalArticle

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Abstract

Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarilytargeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generationSSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone inpatients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1: 1 to receive a combination of everolimus (10 mg/day, orally) andpasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSAuse, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival(PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker responsewas evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographicsand disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8months incombination arm versus 16.6months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses wereobserved in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar(77.2% versus 82.7%, respectively). No significant improvement was observed inmedian overall survival. Adverse events were consistentwith the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared witheverolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

Original languageEnglish
Article numbermdx078
Pages (from-to)1309-1315
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number6
DOIs
Publication statusPublished - Jun 1 2017

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Neuroendocrine Tumors
Disease-Free Survival
Somatostatin
Safety
Chromogranin A
Somatostatin Receptors
Survival
Everolimus
pasireotide
Phosphopyruvate Hydratase
Hyperglycemia
Inpatients
Fasting
Biomarkers
Confidence Intervals
Growth
Serum
Pharmaceutical Preparations

Keywords

  • Everolimus
  • Insulinlike growth factor-1
  • mTOR signaling
  • Pancreatic neuroendocrine tumors
  • Pasireotide LAR
  • Somatostatin analog

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors : COOPERATE-2 trial. / Kulke, M. H.; Ruszniewski, P.; Van Cutsem, E.; Lombard-Bohas, C.; Valle, J. W.; De Herder, W. W.; Pavel, M.; Degtyarev, E.; Brase, J. C.; Bubuteishvili-Pacaud, L.; Voi, M.; Salazar, R.; Borbath, I.; Fazio, N.; Smith, D.; Capdevila, J.; Riechelmann, R. P.; Yao, J. C.

In: Annals of Oncology, Vol. 28, No. 6, mdx078, 01.06.2017, p. 1309-1315.

Research output: Contribution to journalArticle

Kulke, MH, Ruszniewski, P, Van Cutsem, E, Lombard-Bohas, C, Valle, JW, De Herder, WW, Pavel, M, Degtyarev, E, Brase, JC, Bubuteishvili-Pacaud, L, Voi, M, Salazar, R, Borbath, I, Fazio, N, Smith, D, Capdevila, J, Riechelmann, RP & Yao, JC 2017, 'A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial', Annals of Oncology, vol. 28, no. 6, mdx078, pp. 1309-1315. https://doi.org/10.1093/annonc/mdx078
Kulke, M. H. ; Ruszniewski, P. ; Van Cutsem, E. ; Lombard-Bohas, C. ; Valle, J. W. ; De Herder, W. W. ; Pavel, M. ; Degtyarev, E. ; Brase, J. C. ; Bubuteishvili-Pacaud, L. ; Voi, M. ; Salazar, R. ; Borbath, I. ; Fazio, N. ; Smith, D. ; Capdevila, J. ; Riechelmann, R. P. ; Yao, J. C. / A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors : COOPERATE-2 trial. In: Annals of Oncology. 2017 ; Vol. 28, No. 6. pp. 1309-1315.
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abstract = "Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarilytargeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generationSSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone inpatients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1: 1 to receive a combination of everolimus (10 mg/day, orally) andpasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSAuse, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival(PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker responsewas evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographicsand disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8months incombination arm versus 16.6months in everolimus arm (hazard ratio, 0.99; 95{\%} confidence interval, 0.64-1.54). Partial responses wereobserved in 20.3{\%} versus 6.2{\%} of patients in combination arm versus everolimus arm; however, overall disease control rate was similar(77.2{\%} versus 82.7{\%}, respectively). No significant improvement was observed inmedian overall survival. Adverse events were consistentwith the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37{\%} versus 11{\%} of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared witheverolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.",
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TY - JOUR

T1 - A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors

T2 - COOPERATE-2 trial

AU - Kulke, M. H.

AU - Ruszniewski, P.

AU - Van Cutsem, E.

AU - Lombard-Bohas, C.

AU - Valle, J. W.

AU - De Herder, W. W.

AU - Pavel, M.

AU - Degtyarev, E.

AU - Brase, J. C.

AU - Bubuteishvili-Pacaud, L.

AU - Voi, M.

AU - Salazar, R.

AU - Borbath, I.

AU - Fazio, N.

AU - Smith, D.

AU - Capdevila, J.

AU - Riechelmann, R. P.

AU - Yao, J. C.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarilytargeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generationSSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone inpatients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1: 1 to receive a combination of everolimus (10 mg/day, orally) andpasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSAuse, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival(PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker responsewas evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographicsand disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8months incombination arm versus 16.6months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses wereobserved in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar(77.2% versus 82.7%, respectively). No significant improvement was observed inmedian overall survival. Adverse events were consistentwith the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared witheverolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

AB - Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarilytargeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generationSSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone inpatients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1: 1 to receive a combination of everolimus (10 mg/day, orally) andpasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSAuse, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival(PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker responsewas evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographicsand disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8months incombination arm versus 16.6months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses wereobserved in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar(77.2% versus 82.7%, respectively). No significant improvement was observed inmedian overall survival. Adverse events were consistentwith the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared witheverolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

KW - Everolimus

KW - Insulinlike growth factor-1

KW - mTOR signaling

KW - Pancreatic neuroendocrine tumors

KW - Pasireotide LAR

KW - Somatostatin analog

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DO - 10.1093/annonc/mdx078

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