title: Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer.
abstract: OBJECTIVE
  Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer.
  
  
  METHODS
  Patients were randomly assigned to first- or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS).
  
  
  RESULTS
  In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand- foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively).
  
  
  CONCLUSIONS
  Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA. jbaselga@partners.org
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: José Getúlio Martins
authors.initials: JG
authors.lastname: Segalla
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.forename: Auro
authors.initials: A
authors.lastname: Del Giglio
authors.forename: Hélio
authors.initials: H
authors.lastname: Pinczowski
authors.forename: Eva M
authors.initials: EM
authors.lastname: Ciruelos
authors.forename: Sebastião Cabral
authors.initials: SC
authors.lastname: Filho
authors.forename: Patricia
authors.initials: P
authors.lastname: Gómez
authors.forename: Brigitte
authors.initials: B
authors.lastname: Van Eyll
authors.forename: Begoña
authors.initials: B
authors.lastname: Bermejo
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart
authors.forename: Bernardo
authors.initials: B
authors.lastname: Garicochea
authors.forename: Miguel Ángel Climent
authors.initials: MÁ
authors.lastname: Durán
authors.forename: Paulo Marcelo Gehm
authors.initials: PM
authors.lastname: Hoff
authors.forename: Marc
authors.initials: M
authors.lastname: Espié
authors.forename: Andre Augusto Junior Gemeinder
authors.initials: AA
authors.lastname: de Moraes
authors.forename: Ronaldo Albuquerque
authors.initials: RA
authors.lastname: Ribeiro
authors.forename: Clarissa
authors.initials: C
authors.lastname: Mathias
authors.forename: Miguel
authors.initials: M
authors.lastname: Gil Gil
authors.forename: Belén
authors.initials: B
authors.lastname: Ojeda
authors.forename: Josefa
authors.initials: J
authors.lastname: Morales
authors.forename: Sunhee
authors.initials: S
authors.lastname: Kwon Ro
authors.forename: Shell
authors.initials: S
authors.lastname: Li
authors.forename: Frederico
authors.initials: F
authors.lastname: Costa
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000032:analysis*; D001938:Brazil; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000077157:Sorafenib; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; C508053:ERBB2 protein, human