title: A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.
abstract: 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.
  
  
  METHODS
  Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK; The Royal Free NHS Foundation Trust, London, UK. Electronic address: thomas.powles@bartshealth.nhs.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheater
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: Omar
authors.initials: O
authors.lastname: Din
authors.affiliation: Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geldart
authors.affiliation: The Royal Free NHS Foundation Trust, London, UK.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Boleti
authors.affiliation: Arden Cancer Centre, University Hospital, Coventry, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stockdale
authors.affiliation: Nottingham University Hospitals NHS trust, Nottingham, UK.
authors.forename: Santhanam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Sussex Cancer Centre, Brighton, UK.
authors.forename: Angus
authors.initials: A
authors.lastname: Robinson
authors.affiliation: Southend NHS Trust, Southend, UK.
authors.forename: Imtiaz
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK.
authors.forename: Akhila
authors.initials: A
authors.lastname: Wimalasingham
authors.affiliation: AstraZeneca UK Limited, Quantitative Clinical Pharmacology, Macclesfield, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Burke
authors.affiliation: Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK.
authors.forename: Shah-Jalal
authors.initials: SJ
authors.lastname: Sarker
authors.affiliation: University of Liverpool, Clatterbridge Cancer Centre, Liverpool, UK.
authors.forename: Syed
authors.initials: S
authors.lastname: Hussain
authors.affiliation: St. James's University Hospital, University of Leeds, Leeds, UK.
authors.forename: Christy
authors.initials: C
authors.lastname: Ralph
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009025:Morpholines; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C585537:vistusertib; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Renal cancer; Survival; TORC2; mTOR