title: Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE).
abstract: BACKGROUND
  The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs.
  
  
  METHODS
  This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated.
  
  
  RESULTS
  A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively].
  
  
  CONCLUSIONS
  Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201).
  
  
  BACKGROUND
  NCT01280201.
authors.affiliation: Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid. Electronic address: egrande@oncologiahrc.com.
authors.forename: E
authors.initials: E
authors.lastname: Grande
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona.
authors.forename: J
authors.initials: J
authors.lastname: Capdevila
authors.affiliation: Department of Medical Oncology, I + 12 Research Institute, 12 de Octubre University Hospital, Madrid.
authors.forename: D
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Department of Medical Oncology, IDIBELL, Catalan Institute of Oncology L'Hospitalet, Barcelona.
authors.forename: A
authors.initials: A
authors.lastname: Teulé
authors.affiliation: Department of Medical Oncology, Instituto de Biomedicina de Sevilla (IBIS) [HUVR, CSIC, University of Seville], Virgen del Rocío University Hospital, Seville.
authors.forename: I
authors.initials: I
authors.lastname: Durán
authors.affiliation: Department of Medical Oncology, Son Espases Hospital, Palma de Mallorca.
authors.forename: J
authors.initials: J
authors.lastname: Fuster
authors.affiliation: Department of Medical Oncology, Virgen de la Victoria University Hospital, Malaga.
authors.forename: I
authors.initials: I
authors.lastname: Sevilla
authors.affiliation: Department of Medical Oncology, Clínico Lozano Blesa University Hospital, Zaragoza.
authors.forename: P
authors.initials: P
authors.lastname: Escudero
authors.affiliation: Department of Medical Oncology, Clínico San Carlos Hospital, Madrid.
authors.forename: J
authors.initials: J
authors.lastname: Sastre
authors.affiliation: Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Madrid.
authors.forename: J
authors.initials: J
authors.lastname: García-Donas
authors.affiliation: Tumor Angiogenesis Group, IDIBELL, Catalan Institute of Oncology L'Hospitalet, Barcelona.
authors.forename: O
authors.initials: O
authors.lastname: Casanovas
authors.affiliation: Department of Medical Oncology Research Laboratory, Ramón y Cajal University Hospital, Madrid.
authors.forename: J
authors.initials: J
authors.lastname: Earl
authors.affiliation: Department of Pathology, Clínico San Carlos Hospital, Madrid.
authors.forename: L
authors.initials: L
authors.lastname: Ortega
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, ISCIII Center for Biomedical Research on Rare Disease (CIBERER) Madrid, Madrid.
authors.forename: M
authors.initials: M
authors.lastname: Apellaniz-Ruiz
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, ISCIII Center for Biomedical Research on Rare Disease (CIBERER) Madrid, Madrid.
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez-Antona
authors.affiliation: Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid.
authors.forename: T
authors.initials: T
authors.lastname: Alonso-Gordoa
authors.affiliation: Department of Endocrinology, Ramón y Cajal University Hospital, Madrid, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Díez
authors.affiliation: Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid.
authors.forename: A
authors.initials: A
authors.lastname: Carrato
authors.affiliation: Department of Medical Oncology, Instituto de Biomedicina de Sevilla (IBIS) [HUVR, CSIC, University of Seville], Virgen del Rocío University Hospital, Seville.
authors.forename: R
authors.initials: R
authors.lastname: García-Carbonero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: angiogenic markers; bronchial carcinoids; gastroenteropancreatic tumors; pazopanib; polymorphisms; thymic tumors