title: A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer.
abstract: BACKGROUND
  We conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer.
  
  
  METHODS
  Patients were randomised to paclitaxel (90mg/m(2), weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ≤ 0.82 (1-sided α=0.14) after 120 events supporting a treatment effect.
  
  
  RESULTS
  Patients were randomised in India (n=170), the United States (n=52) and Brazil (n=15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR)=0.788; 95% confidence interval (CI), 0.558-1.112; P=0.1715 [1-sided P=0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR=0.674; 95% CI 0.465-0.975; P=0.0343) and improved overall response (67% versus 54%; P=0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR=1.022; 95% CI 0.715-1.461; P=0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm.
  
  
  CONCLUSIONS
  The addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. w-gradishar@northwestern.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Gradishar
authors.forename: Virginia
authors.initials: V
authors.lastname: Kaklamani
authors.forename: Tarini P
authors.initials: TP
authors.lastname: Sahoo
authors.forename: Dasappa
authors.initials: D
authors.lastname: Lokanatha
authors.forename: Vinod
authors.initials: V
authors.lastname: Raina
authors.forename: Shailesh
authors.initials: S
authors.lastname: Bondarde
authors.forename: Minish
authors.initials: M
authors.lastname: Jain
authors.forename: Sunhee Kwon
authors.initials: SK
authors.lastname: Ro
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Lokker
authors.forename: Lee
authors.initials: L
authors.lastname: Schwartzberg
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000627:therapeutic use; D000077157:Sorafenib
chemical_list: D009536:Niacinamide; D017239:Paclitaxel; D010671:Phenylurea Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib