title: Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.
abstract: BACKGROUND
  Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma.
  
  
  METHODS
  We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445.
  
  
  RESULTS
  Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none).
  
  
  CONCLUSIONS
  In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors.
  
  
  BACKGROUND
  Novartis and Pfizer.
authors.affiliation: Duke University and the Duke Cancer Institute, Durham, NC, USA. Electronic address: andrew.armstrong@duke.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Duke University and the Duke Cancer Institute, Durham, NC, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Halabi
authors.affiliation: University of Cambridge, Cambridge, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Eisen
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Broderick
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: University of Glasgow, The Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.affiliation: Washington University in St Louis, St Louis, MO, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.affiliation: Christie Cancer Research Centre, Manchester, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.affiliation: BC Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Kollmannsberger
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Logan
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Pickering
authors.affiliation: Oregon Health & Science University, OHSU Knight Cancer Institute, Portland, OR, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
authors.affiliation: University of Oxford Medical Oncology Department, Oxford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Protheroe
authors.affiliation: inVentiv Health Clinical, Princeton, NJ, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lusk
authors.affiliation: inVentiv Health Clinical, Princeton, NJ, USA.
authors.forename: Sadie
authors.initials: S
authors.lastname: Oberg
authors.affiliation: Duke University and the Duke Cancer Institute, Durham, NC, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D000077210:Sunitinib; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib