title: Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial.
abstract: BACKGROUND
  An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma.
  
  
  METHODS
  In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027.
  
  
  RESULTS
  284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively).
  
  
  CONCLUSIONS
  Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting.
  
  
  BACKGROUND
  Novartis Pharmaceuticals Corporation.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: motzerr@mskcc.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo University Hospital Foundation, Pavia, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.affiliation: San Camillo and Forlanini Hospitals, Rome, Italy.
authors.forename: Cora N
authors.initials: CN
authors.lastname: Sternberg
authors.affiliation: Military Institute of Health Services in Warsaw, Warsaw, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.affiliation: Maria Sklodowska-Curie Institute, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Zolnierek
authors.affiliation: BC Cancer Agency Vancouver Cancer Centre, Vancouver, BC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
authors.affiliation: Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.affiliation: Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: De Giorgi
authors.affiliation: Hanover Medical School, Hanover, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Grünwald
authors.affiliation: Monash University Eastern Health Clinical School, Melbourne, VIC, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.affiliation: Asan Medical Center, Seoul, South Korea.
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.affiliation: Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Esteban
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Urbanowitz
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Cai
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Squires
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Marker
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shi
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib