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.
Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET.



Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, 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 response was evaluated in an exploratory analysis.



Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed 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 in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively.



The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
M H
MH
Kulke
Department of Gastroenterology and Pancreatology University of Paris VII and Beaujon Hospital, Paris, France.
P
P
Ruszniewski
Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium.
E
E
Van Cutsem
Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France.
C
C
Lombard-Bohas
Department of Medical Oncology, University of Manchester/The Christie Hospital, Manchester, UK.
J W
JW
Valle
Department of Endocrine Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
W W
WW
De Herder
Department of Hepatology and Gastroenterology, Charité University of Medicine, Berlin, Germany.
M
M
Pavel
Department of Oncology, Novartis AG, Basel, Switzerland.
E
E
Degtyarev
Department of Oncology, Novartis AG, Basel, Switzerland.
J C
JC
Brase
Department of Oncology, Novartis AG, Basel, Switzerland.
L
L
Bubuteishvili-Pacaud
Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, USA.
M
M
Voi
Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, Hospital of Barcelona, Barcelona, Spain.
R
R
Salazar
Department of Gastroenterology Saint-Luc University Hospital, Brussels, Belgium.
I
I
Borbath
Department of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.
N
N
Fazio
Department of Oncology, St. Andrew Hospital, Bordeaux, France.
D
D
Smith
Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
J
J
Capdevila
Department of Oncology, Cancer Institute of the State of São Paulo, São Paulo, Brazil.
R P
RP
Riechelmann
Department of Gastrointestinal and Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
J C
JC
Yao
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018450:Disease Progression; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016019:Survival Analysis; D055815:Young Adult
D013004:Somatostatin; C517782:pasireotide; D000068338:Everolimus
everolimus; insulin-like growth factor-1; mTOR signaling; pancreatic neuroendocrine tumors; pasireotide LAR; somatostatin analog