title: EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.
abstract: BACKGROUND
  We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC).
  
  
  METHODS
  A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome.
  
  
  RESULTS
  We recruited 55 eligible participants from September 2010 to August 2012.
  
  
  METHODS
  mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified.
  
  
  CONCLUSIONS
  The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.
  
  
  BACKGROUND
  ACTRN12609000643279.
authors.affiliation: Monash University Eastern Health Clinical School, Melbourne; ANZUP Cancer Trials Group, Sydney. Electronic address: ian.davis@monash.edu.
authors.forename: I D
authors.initials: ID
authors.lastname: Davis
authors.affiliation: ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney.
authors.forename: A
authors.initials: A
authors.lastname: Long
authors.affiliation: ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney.
authors.forename: S
authors.initials: S
authors.lastname: Yip
authors.affiliation: ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney.
authors.forename: D
authors.initials: D
authors.lastname: Espinoza
authors.affiliation: ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney.
authors.forename: J F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Flinders Centre for Innovation in Cancer, Flinders University, Adelaide.
authors.forename: G
authors.initials: G
authors.lastname: Kichenadasse
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Sydney; Liverpool Hospital, Liverpool.
authors.forename: M
authors.initials: M
authors.lastname: Harrison
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Royal Hobart Hospital and Menzies Institute for Medical Research, University of Tasmania, Hobart.
authors.forename: R M
authors.initials: RM
authors.lastname: Lowenthal
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Royal North Shore Hospital, University of Sydney, Sydney.
authors.forename: N
authors.initials: N
authors.lastname: Pavlakis
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Austin Health, Melbourne.
authors.forename: A
authors.initials: A
authors.lastname: Azad
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Ballarat Oncology & Haematology Services and Fiona Elsey Cancer Research Institute, Ballarat; Federation University, Ballarat.
authors.forename: G
authors.initials: G
authors.lastname: Kannourakis
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Border Medical Oncology, Wodonga.
authors.forename: C
authors.initials: C
authors.lastname: Steer
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Prince of Wales Clinical School and Prince of Wales Hospital, University of New South Wales, Sydney.
authors.forename: D
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Cabrini Hospital, Melbourne.
authors.forename: J
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Bill Walsh Translational Cancer Research Laboratories, Kolling Institute, Sydney.
authors.forename: R
authors.initials: R
authors.lastname: Harvie
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane.
authors.forename: L
authors.initials: L
authors.lastname: Jovanovic
authors.affiliation: Bill Walsh Translational Cancer Research Laboratories, Kolling Institute, Sydney.
authors.forename: A L
authors.initials: AL
authors.lastname: Hudson
authors.affiliation: ANZUP Cancer Trials Group, Sydney; Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane.
authors.forename: C C
authors.initials: CC
authors.lastname: Nelson
authors.affiliation: ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney; Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, Sydney; Concord Cancer Centre, Concord, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Stockler
authors.affiliation: ANZUP Cancer Trials Group, Sydney; NHMRC Clinical Trials Centre, University of Sydney, Sydney; Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Sydney.
authors.forename: A
authors.initials: A
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001315:Australia; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012307:Risk Factors; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000068338:Everolimus; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib
keywords: angiogenesis inhibitors; clinical trial; everolimus; renal cell carcinoma; sunitinib; vascular endothelial growth factor receptors