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Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma

Byline: Charles S. Harmon (1,9), Samuel E. DePrimo (1,10), Robert A. Figlin (2), Gary R. Hudes (3), Thomas E. Hutson (4), M. Dror Michaelson (5), Sylvie Negrier (6), Sindy T. Kim (1), Xin Huang (1), J. Andrew Williams (1), Tim Eisen (7), Robert J. Motzer (8) Keywords: Metastatic renal cell carcinoma... Full description

Journal Title: Cancer Chemotherapy and Pharmacology 2014, Vol.73(1), pp.151-161
Main Author: Harmon, Charles
Other Authors: DePrimo, Samuel , Figlin, Robert , Hudes, Gary , Hutson, Thomas , Michaelson, M. , Négrier, Sylvie , Kim, Sindy , Huang, Xin , Williams, J. , Eisen, Tim , Motzer, Robert
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0344-5704 ; E-ISSN: 1432-0843 ; DOI: 10.1007/s00280-013-2333-4
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recordid: springer_jour10.1007/s00280-013-2333-4
title: Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma
format: Article
creator:
  • Harmon, Charles
  • DePrimo, Samuel
  • Figlin, Robert
  • Hudes, Gary
  • Hutson, Thomas
  • Michaelson, M.
  • Négrier, Sylvie
  • Kim, Sindy
  • Huang, Xin
  • Williams, J.
  • Eisen, Tim
  • Motzer, Robert
subjects:
  • Metastatic renal cell carcinoma
  • Sunitinib
  • Biomarkers
  • Phase III clinical trial
ispartof: Cancer Chemotherapy and Pharmacology, 2014, Vol.73(1), pp.151-161
description: Byline: Charles S. Harmon (1,9), Samuel E. DePrimo (1,10), Robert A. Figlin (2), Gary R. Hudes (3), Thomas E. Hutson (4), M. Dror Michaelson (5), Sylvie Negrier (6), Sindy T. Kim (1), Xin Huang (1), J. Andrew Williams (1), Tim Eisen (7), Robert J. Motzer (8) Keywords: Metastatic renal cell carcinoma; Sunitinib; Biomarkers; Phase III clinical trial Abstract: Purpose We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-[alpha]), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8. Methods Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-[alpha] 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1--4 and at end of treatment were analyzed by ELISA. Results Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-[alpha] (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS) in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS in the IFN-[alpha] arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-[alpha] arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated. Conclusions Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy. Author Affiliation: (1) Pfizer Oncology, 10646 Science Center Drive, La Jolla, San Diego, CA, 92121, USA (2) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA (3) Fox Chase Cancer Center, Philadelphia, PA, USA (4) Baylor Sammons Cancer Center-Texas Oncology, P.A., Dallas, TX, USA (5) Massachusetts General Hospital Cancer Center, Boston, MA, USA (6)
language: eng
source:
identifier: ISSN: 0344-5704 ; E-ISSN: 1432-0843 ; DOI: 10.1007/s00280-013-2333-4
fulltext: fulltext_linktorsrc
issn:
  • 1432-0843
  • 14320843
  • 0344-5704
  • 03445704
url: Link


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titleCirculating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma
creatorHarmon, Charles ; DePrimo, Samuel ; Figlin, Robert ; Hudes, Gary ; Hutson, Thomas ; Michaelson, M. ; Négrier, Sylvie ; Kim, Sindy ; Huang, Xin ; Williams, J. ; Eisen, Tim ; Motzer, Robert
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descriptionByline: Charles S. Harmon (1,9), Samuel E. DePrimo (1,10), Robert A. Figlin (2), Gary R. Hudes (3), Thomas E. Hutson (4), M. Dror Michaelson (5), Sylvie Negrier (6), Sindy T. Kim (1), Xin Huang (1), J. Andrew Williams (1), Tim Eisen (7), Robert J. Motzer (8) Keywords: Metastatic renal cell carcinoma; Sunitinib; Biomarkers; Phase III clinical trial Abstract: Purpose We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-[alpha]), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8. Methods Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-[alpha] 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1--4 and at end of treatment were analyzed by ELISA. Results Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-[alpha] (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS) in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS in the IFN-[alpha] arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-[alpha] arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated. Conclusions Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy. Author Affiliation: (1) Pfizer Oncology, 10646 Science Center Drive, La Jolla, San Diego, CA, 92121, USA (2) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA (3) Fox Chase Cancer Center, Philadelphia, PA, USA (4) Baylor Sammons Cancer Center-Texas Oncology, P.A., Dallas, TX, USA (5) Massachusetts General Hospital Cancer Center, Boston, MA, USA (6) Centre Leon Berard, Lyon, France (7) Cambridge University Health Partners, Addenbrooke's Hospital, Cambridge, UK (8) Memorial Sloan-Kettering Cancer Center, New York, NY, USA (9) Independent Consultant, San Diego, CA, USA (10) Janssen Research and Development, San Diego, CA, USA Article History: Registration Date: 18/10/2013 Received Date: 02/05/2013 Accepted Date: 17/10/2013 Online Date: 13/11/2013
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