title: Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma.
abstract: This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib.
  
  
  
  In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points.
  
  
  
  Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies.
  
  
  
  In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.
authors.affiliation: Thomas E. Hutson, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX; Bernard Escudier, Institut Gustave Roussy, Villejuif, France; Emilio Esteban, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain; Georg A. Bjarnason, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada; Ho Yeong Lim, Samsung Medical Center, Seoul, Korea; Kenneth B. Pittman, The Queen Elizabeth Hospital, Woodville South, Adelaide, Australia; Peggy Senico, Pfizer, Collegeville, PA; Andreas Niethammer and Dongrui Ray Lu Pfizer, La Jolla, CA; Subramanian Hariharan, Pfizer; and Robert J. Motzer, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Emilio
authors.initials: E
authors.lastname: Esteban
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Pittman
authors.forename: Peggy
authors.initials: P
authors.lastname: Senico
authors.forename: Andreas
authors.initials: A
authors.lastname: Niethammer
authors.forename: Dongrui Ray
authors.initials: DR
authors.lastname: Lu
authors.forename: Subramanian
authors.initials: S
authors.lastname: Hariharan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077157:Sorafenib; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; C401859:temsirolimus; D000077157:Sorafenib; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib; D020123:Sirolimus