A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK)

Powles, T. et al. (2016) A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK). Annals of Oncology, 27(5), pp. 880-886. (doi: 10.1093/annonc/mdw014) (PMID:26802156)

Abstract

Background Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. Patients and methods Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel–Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. Results Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6–7.3 months) for C and 3.9 (2.4–5.3 months) for CS; hazard ratio (HR) 1.18 (0.94–1.48)] or overall survival (OS) [14.2 months (11.2–16.8 months) for C and 10.0 (6.7–13.2 months) for CS; HR 1.28 (1.00–1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09–4.82), P >>0.05], but not PFS, for CS. Conclusions Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers.

• Item Type: Articles
• Additional Information: This study was funded by Cancer Research UK and AstraZeneca (grant 2009-018014-20). It was sponsored by CaCTUS, Scottish Clinical Trials Research Unit.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jones, Professor Robert
• Authors: Powles, T., Brown, J., Larkin, J., Jones, R., Ralph, C., Hawkins, R., Chowdhury, S., Boleti, E., Bhal, A., Fife, K., Webb, A., Crabb, S., Geldart, T., Hill, R., Dunlop, J., Hall, P. E., McLaren, D., Ackerman, C., Beltran, L., and Nathan, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Annals of Oncology
• Publisher: Oxford University Press
• ISSN: 0923-7534
• ISSN (Online): 1569-8041
• Published Online: 22 January 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Annals of Oncology 27(5):880-886
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher