title: Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab.
abstract: OBJECTIVE
  We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.
  
  
  METHODS
  This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).
  
  
  RESULTS
  One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).
  
  
  CONCLUSIONS
  The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions.
authors: West Clinic, Memphis, Tennessee, USA.
authors: Lee S
authors: LS
authors: Schwartzberg
authors: Kurt W
authors: KW
authors: Tauer
authors: Robert C
authors: RC
authors: Hermann
authors: Grace
authors: G
authors: Makari-Judson
authors: Claudine
authors: C
authors: Isaacs
authors: J Thaddeus
authors: JT
authors: Beck
authors: Virginia
authors: V
authors: Kaklamani
authors: Edward J
authors: EJ
authors: Stepanski
authors: Hope S
authors: HS
authors: Rugo
authors: Wei
authors: W
authors: Wang
authors: Katherine
authors: K
authors: Bell-McGuinn
authors: Jeffrey J
authors: JJ
authors: Kirshner
authors: Peter
authors: P
authors: Eisenberg
authors: Richard
authors: R
authors: Emanuelson
authors: Mark
authors: M
authors: Keaton
authors: Ellis
authors: E
authors: Levine
authors: Diana C
authors: DC
authors: Medgyesy
authors: Rubina
authors: R
authors: Qamar
authors: Alexander
authors: A
authors: Starr
authors: Sunhee Kwon
authors: SK
authors: Ro
authors: Nathalie A
authors: NA
authors: Lokker
authors: Clifford A
authors: CA
authors: Hudis
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012871:Skin Diseases / Q000139:chemically induced; D000077157:Sorafenib; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D009536:Niacinamide; D010671:Phenylurea Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; D000093542:Gemcitabine