title: Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial.
abstract: BACKGROUND
  Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy.
  
  
  METHODS
  In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379.
  
  
  RESULTS
  Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone.
  
  
  CONCLUSIONS
  These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: German Breast Group, Neu-Isenburg, and University Women's Hospital, Frankfurt, Germany. Electronic address: Gunter.vonMinckwitz@germanbreastgroup.de.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
authors.affiliation: University Hospital of Udine, Udine, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Puglisi
authors.affiliation: Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortes
authors.affiliation: Center of Oncology, University Hospital Split, Split, Croatia.
authors.forename: Eduard
authors.initials: E
authors.lastname: Vrdoljak
authors.affiliation: Outpatient Cancer Center, Freiburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Marschner
authors.affiliation: Department of Medicine I and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria; Central European Cooperative Oncology Group, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Zielinski
authors.affiliation: Centre Hospitalier-Universitaire de Besançon, Besançon, France.
authors.forename: Cristian
authors.initials: C
authors.lastname: Villanueva
authors.affiliation: Institut du Cancer Montpellier, Val d'Aurelle, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.affiliation: National Institute of Oncology, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Lang
authors.affiliation: Hospital Universitario 12 Octubre, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.affiliation: Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: De Laurentiis
authors.affiliation: Centre Henri Becquerel, Rouen, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Veyret
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: de Ducla
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Freudensprung
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Srock
authors.affiliation: Assistance-Publique Hôpitaux de Paris-Tenon, Institut Universitaire de Cancerologie Université Pierre et Marie Curie, Sorbonne Université, Paris, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gligorov
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D018734:Genes, erbB-2 / Q000235:genetics; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D018579:Patient Selection; D012074:Remission Induction / Q000379:methods; D019233:Retreatment; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab