title: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.
abstract: BACKGROUND
  Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.
  
  
  METHODS
  We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.
  
  
  RESULTS
  Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.
  
  
  CONCLUSIONS
  Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).
authors.affiliation: From the Dana-Farber Cancer Institute, Boston (T.K.C., P.W.K.); Institut Gustave Roussy, Villejuif, France (B.E.); Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London (T.P.); Icon Cancer Care, South Brisbane, QLD, Australia (P.N.M.); Cleveland Clinic, Cleveland (B.I.R.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (H.H.); Texas Oncology-Charles A. Sammons Cancer Center, Baylor University, Dallas (T.E.H.); University of Ulsan College of Medicine (J.-L.L.) and Seoul National University Hospital (B.K.) - both in Seoul, South Korea; Helsinki University Central Hospital Cancer Center, Helsinki (K.P.); Washington University in St. Louis, St. Louis (B.J.R.); Sunnybrook Odette Cancer Centre, Toronto (G.A.B.), and Tom Baker Cancer Centre, Calgary, AB (D.Y.C.H.) - both in Canada; National Institute of Oncology, Budapest, Hungary (L.G.); Hospital de la Santa Creu i Sant Pau, Barcelona (P.M.); Medical University of Vienna, Vienna (M.S.); Exelixis, South San Francisco, CA (A.B-H., C.H., C.S., G.M.S.); University of Texas M.D. Anderson Cancer Center, Houston (N.M.T.); and the Memorial Sloan Kettering Cancer Center, New York (R.J.M.).
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mainwaring
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Frede
authors.initials: F
authors.lastname: Donskov
authors.forename: Hans
authors.initials: H
authors.lastname: Hammers
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.forename: Katriina
authors.initials: K
authors.lastname: Peltola
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Roth
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.forename: Lajos
authors.initials: L
authors.lastname: Géczi
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.forename: Pablo
authors.initials: P
authors.lastname: Maroto
authors.forename: Daniel Y C
authors.initials: DY
authors.lastname: Heng
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmidinger
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Anne
authors.initials: A
authors.lastname: Borgman-Hagey
authors.forename: Colin
authors.initials: C
authors.lastname: Hessel
authors.forename: Christian
authors.initials: C
authors.lastname: Scheffold
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Schwab
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016019:Survival Analysis
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; C558660:cabozantinib; D000068338:Everolimus; D020123:Sirolimus