A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer

Abstract

BackgroundEverolimus 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). ObjectiveThe 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 participantsPatients with measurable mRCC and VEGF-refractory disease were eligible for this trial. InterventionStarting 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. Outcome measurements and statistical analysisProgression-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 limitationsRecruitment 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). ConclusionsThe PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. Patient summaryThere 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.