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Updated: Mar 26, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with
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.
Clinicaltrialsgov:
NCT00942877.
Insights
Adding the SRC inhibitor saracatinib to vascular endothelial growth factor (VEGF) targeted therapy did not improve outcomes for patients with metastatic clear-cell renal cancer (mRCC). Biomarker analysis did not reveal predictive markers for treatment response.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Preclinical studies suggested SRC proteins contribute to resistance against VEGF-targeted therapy in metastatic clear-cell renal cancer (mRCC).
- This led to investigating the efficacy of combining a SRC inhibitor (saracatinib) with a VEGF inhibitor (cediranib).
Purpose of the Study:
- To evaluate if combining cediranib with saracatinib improves progression-free survival (PFS) in mRCC patients who progressed on prior VEGF-targeted therapy.
- To identify potential biomarkers predictive of treatment response.
Main Methods:
- A double-blind, randomized phase II study compared cediranib plus saracatinib (CS) versus cediranib plus placebo (C).
- 138 patients with mRCC and prior VEGF-targeted therapy were enrolled.
- Archived tissue samples were analyzed for biomarkers including SRC, FAK, and HIF-2α.
Main Results:
- No significant difference in PFS or overall survival (OS) was observed between the CS and C groups.
- Partial response rates were similar in both arms (14.5% for CS vs. 13.0% for C).
- FAK overexpression showed a trend towards OS benefit with CS, but was not prognostic for PFS.
Conclusions:
- Saracatinib did not enhance the efficacy of cediranib in this patient population.
- No consistent predictive biomarkers for treatment efficacy were identified in this study.
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