E Grande1, J Capdevila2, D Castellano3, A Teulé4, I Durán5, J Fuster6, I Sevilla7, P Escudero8, J Sastre9, J García-Donas10, O Casanovas11, J Earl12, L Ortega13, M Apellaniz-Ruiz14, C Rodriguez-Antona14, T Alonso-Gordoa15, J J Díez16, A Carrato15, R García-Carbonero5. 1. Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid. Electronic address: egrande@oncologiahrc.com. 2. Department of Medical Oncology, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona. 3. Department of Medical Oncology, I + 12 Research Institute, 12 de Octubre University Hospital, Madrid. 4. Department of Medical Oncology, IDIBELL, Catalan Institute of Oncology L'Hospitalet, Barcelona. 5. Department of Medical Oncology, Instituto de Biomedicina de Sevilla (IBIS) [HUVR, CSIC, University of Seville], Virgen del Rocío University Hospital, Seville. 6. Department of Medical Oncology, Son Espases Hospital, Palma de Mallorca. 7. Department of Medical Oncology, Virgen de la Victoria University Hospital, Malaga. 8. Department of Medical Oncology, Clínico Lozano Blesa University Hospital, Zaragoza. 9. Department of Medical Oncology, Clínico San Carlos Hospital, Madrid. 10. Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Madrid. 11. Tumor Angiogenesis Group, IDIBELL, Catalan Institute of Oncology L'Hospitalet, Barcelona. 12. Department of Medical Oncology Research Laboratory, Ramón y Cajal University Hospital, Madrid. 13. Department of Pathology, Clínico San Carlos Hospital, Madrid. 14. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, ISCIII Center for Biomedical Research on Rare Disease (CIBERER) Madrid, Madrid. 15. Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid. 16. Department of Endocrinology, Ramón y Cajal University Hospital, Madrid, Spain.
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). CLINICAL TRIAL NUMBER: NCT01280201.
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 VEGFR3rs307821 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). CLINICAL TRIAL NUMBER: NCT01280201.
Authors: J Capdevila; O Casanovas; R Salazar; D Castellano; A Segura; P Fuster; J Aller; R García-Carbonero; P Jimenez-Fonseca; E Grande; J P Castaño Journal: Oncogene Date: 2016-09-19 Impact factor: 9.867
Authors: James C Yao; Marianne Pavel; Catherine Lombard-Bohas; Eric Van Cutsem; Maurizio Voi; Ulrike Brandt; Wei He; David Chen; Jaume Capdevila; Elisabeth G E de Vries; Paola Tomassetti; Timothy Hobday; Rodney Pommier; Kjell Öberg Journal: J Clin Oncol Date: 2016-09-30 Impact factor: 44.544