Powles T., Wheater M., Din O., Geldart T., Boleti E., Stockdale A., Sundar S., Robinson A., Ahmed I., Wimalasingham A., Burke W., Sarker S.-J., Hussain S., Ralph C.
European Urology 2015
Background: 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). Objective: 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. Design, setting, and participants: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. Intervention: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50. mg twice daily) or everolimus (10. mg once daily) until progression of disease at 10 centres across the United Kingdom. Outcome measurements and statistical analysis: 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. Results and limitations: 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 <. 0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p = 0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p <. 0.02). Conclusions: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. Patient summary: 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. This study is the first randomised trial to show that AZD2014 (a TORC1 and TORC2 inhibitor) was less active than everolimus (TORC1 inhibitor) in metastatic renal cell carcinoma. This study contradicts preclinical data that support the use of broader spectrum mammalian target of rapamycin inhibitors.