title: Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.
abstract: OBJECTIVE
  Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas.
  
  
  METHODS
  Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability.
  
  
  RESULTS
  A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%).
  
  
  CONCLUSIONS
  Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.
authors.affiliation: Ludwig Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Sant P
authors.initials: SP
authors.lastname: Chawla
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Staddon
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Milhem
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
authors.forename: Richard F
authors.initials: RF
authors.lastname: Riedel
authors.forename: Binh
authors.initials: B
authors.lastname: Bui-Nguyen
authors.forename: Lee D
authors.initials: LD
authors.lastname: Cranmer
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bompas
authors.forename: Thierry
authors.initials: T
authors.lastname: Alcindor
authors.forename: Daniel
authors.initials: D
authors.lastname: Rushing
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Ruey-Min
authors.initials: RM
authors.lastname: Lee
authors.forename: Scot
authors.initials: S
authors.lastname: Ebbinghaus
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Eid
authors.forename: John W
authors.initials: JW
authors.lastname: Loewy
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Dodion
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007391:International Cooperation; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000556:secondary*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; C515074:ridaforolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus