Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone).
In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2).
The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC.
Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial.
Starting in February 2013, patients were randomised (1:1) to AZD2014 (50mg twice daily) or everolimus (10mg once daily) until progression of disease at 10 centres across the United Kingdom.
Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients.
Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1. 8 and 4. 6 mo, respectively (hazard ratio: 2. 8 [95% confidence interval (CI), 1. 2-6. 5]; p=0. 01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p
The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles.
There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.
European urology. 2015 Sep 10 [Epub ahead of print]
Thomas Powles, Matthew Wheater, Omar Din, Thomas Geldart, Ekaterini Boleti, Andrew Stockdale, Santhanam Sundar, Angus Robinson, Imtiaz Ahmed, Akhila Wimalasingham, Wendy Burke, Shah-Jalal Sarker, Syed Hussain, Christy Ralph
Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK; The Royal Free NHS Foundation Trust, London, UK. Southampton NHS Foundation Trust, Southampton, UK. , Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. , Royal Bournemouth Hospital, Bournemouth, UK. , The Royal Free NHS Foundation Trust, London, UK. , Arden Cancer Centre, University Hospital, Coventry, UK. , Nottingham University Hospitals NHS trust, Nottingham, UK. , Sussex Cancer Centre, Brighton, UK. , Southend NHS Trust, Southend, UK. , Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK. , AstraZeneca UK Limited, Quantitative Clinical Pharmacology, Macclesfield, UK. , Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK. , University of Liverpool, Clatterbridge Cancer Centre, Liverpool, UK. , St. James's University Hospital, University of Leeds, Leeds, UK.