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

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. (2016) A randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic clear cell renal cancer (COSAK). Annals of Oncology, 27 (5), 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, randomised (1:1) phase II study. The study compared the combination cediranib 30mg once daily (OD) and saracatinib 175mg OD (CS) (n=69) or cediranib 45mg OD and placebo OD (C) (n=69). Archived tissue was used for biomarker analysis (SRC, FAK, VHL, PTB1b and HIF2?: n=86).The primary endpoint was progression free survival (PFS) by RECIST v1.1.

RESULTS: Between 2010 and 2012, 138 patients were randomised 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 respectively (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. Focal adhesion kinase (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.

This record has no associated files available for download.

Contributors

Author: S. Crabb

Download statistics