title: Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting.
  
  
  METHODS
  We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75-100 mg/m(2)) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m(2) twice per day on days 1-14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1·5 vs >1·5 × upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00929240.
  
  
  RESULTS
  Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11·9 months [95% CI 9·8-15·4] vs 4·3 months [3·9-6·8]; stratified hazard ratio 0·38 [95% CI 0·27-0·55]; two-sided log-rank p<0·0001), as was overall survival (median 39·0 months [95% CI 32·3-not reached] vs 23·7 months [18·5-31·7]; stratified HR 0·43 [95% CI 0·26-0·69]; two-sided log-rank p=0·0003). Results for time to progression were consistent with those for progression-free survival. 78 (86%) patients in the bevacizumab and capecitabine group and 72 (77%) in the bevacizumab only group had an objective response. Clinical benefit was recorded in 92 (98%) patients in the bevacizumab alone group and 90 (99%) in the bevacizumab and capecitabine group. Mean change from baseline in global health score did not differ significantly between groups. Grade 3 or worse adverse events during the maintenance phase were more common with bevacizumab and capecitabine than with bevacizumab only (45 [49%] of 91 patients vs 25 [27%] of 92 patients). The most common grade 3 or worse events were hand-foot syndrome (28 [31%] in the bevacizumab and capecitabine group vs none in the bevacizumab alone group), hypertension (eight [9%] vs three [3%]), and proteinuria (three [3%] vs four [4%]). Serious adverse events were reported by ten (11%) patients in the bevacizumab and capecitabine group and seven (8%) patients in the bevacizumab only group.
  
  
  CONCLUSIONS
  Despite prematurely terminated accrual and the lack of information about post-progression treatment, both progression-free survival and overall survival were significantly improved with bevacizumab and capecitabine compared with bevacizumab alone as maintenance treatment. These results might inform future maintenance trials and current first-line treatment strategies for HER2-negative metastatic breast cancer.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Assistance-Publique Hôpitaux de Paris-Tenon, Institut Universitaire de Cancerologie Université Pierre et Marie Curie, Sorbonne Université, Paris, France. Electronic address: joseph.gligorov@tnn.aphp.fr.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gligorov
authors.affiliation: Rajiv Gandhi Cancer Institute & Research Center, Delhi, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Doval
authors.affiliation: Instituto Nacional de Cancer, Rio de Janeiro, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Bines
authors.affiliation: Hospital Universitario Regional y Virgen de la Victoria, IBIMA, Málaga, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Alba
authors.affiliation: University Hospital of Santa Maria, Lisbon, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Cortes
authors.affiliation: Institut Curie, Université Paris Descartes, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Sakra World Hospital, Bangalore, India.
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil.
authors.forename: Rômulo
authors.initials: R
authors.lastname: Costa
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Srock
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: de Ducla
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Freudensprung
authors.affiliation: Medical Oncology, University of Trieste, Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mustacchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D002681:China; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000069287:Capecitabine; D003841:Deoxycytidine; D000077143:Docetaxel; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids