title: Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial.
abstract: The study was designed to evaluate efficacy and superiority of capecitabine/bevacizumab + vinorelbine (CAP/BEV/VIN) compared to CAP/BEV alone. Main purpose was to introduce a taxane-/anthracycline-free first-line treatment in advanced breast cancer (ABC), in order to avoid long-term toxicities. In this open-label, superiority, phase 3 trial, patients with HER2-negative ABC were randomized 1:1 to receive either oral CAP at 1000 mg/m(2) [twice daily, days 1-14, q3w] plus intravenous BEV at 15 mg/kg [day 1, q3w] (arm A) or in addition to this protocol intravenous VIN at 25 mg/m(2) [days 1 + 8, q3w] (arm B) until disease progression, unacceptable toxicity or withdrawal of consent. Between 26 February 2009 and 26 October 2012, we randomised 600 patients (arm A N = 300; arm B N = 300) from 57 German outpatient-centres and 2 university hospitals. Median progression-free survival (PFS) (primary endpoint) was not improved with VIN (CAP/BEV, 8.8 months; CAP/BEV/VIN, 9.6 months; HR 0.84 [95 % CI 0.70-1.01], P = 0.058). Median overall survival (OS) (secondary endpoint) was 25.1 and 27.2 months for CAP/BEV and CAP/BEV/VIN, respectively, average HR 0.85 [95 % CI 0.70-1.03], P = 0.104). The 1- and 2-year OS rates appeared to be similar (78.0 and 77.0 %; 53.0 and 54.0 %). Toxicity profiles were generally mild and manageable. Adverse events occurred more frequently in arm B. Regarding the balance between clinical efficacy (PFS, OS) and toxicity, the CAP/BEV combination provides a favourable treatment option in first-line ABC avoiding taxane- and/or anthracycline-induced long-term toxicity. Superiority of CAP/BEV/VIN was not met, and side effects were even enhanced. Nevertheless, no safety issues occurred.
authors.affiliation: Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Welt
authors.affiliation: Outpatient-Centre for Interdisciplinary Oncology and Haematology, Wirthstrasse 11c, 79110, Freiburg I.Br., Germany. marschner@onkologie-freiburg.de.
authors.forename: N
authors.initials: N
authors.lastname: Marschner
authors.affiliation: Oncology Outpatient-Centre, Muenster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Lerchenmueller
authors.affiliation: Oncology Outpatient-Centre, Ravensburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Decker
authors.affiliation: Oncology Outpatient-Centre, Stade, Germany.
authors.forename: C-C
authors.initials: CC
authors.lastname: Steffens
authors.affiliation: Oncology Outpatient-Centre, Langen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Koehler
authors.affiliation: Oncology Outpatient-Centre, Guetersloh, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Depenbusch
authors.affiliation: IOMEDICO, Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Busies
authors.affiliation: HOPE-Practice for Oncology, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hegewisch-Becker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000069287:Capecitabine / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077235:Vinorelbine
chemical_list: D000068258:Bevacizumab; D000069287:Capecitabine; D018719:Erb-b2 Receptor Tyrosine Kinases; D014747:Vinblastine; D000077235:Vinorelbine; C508053:ERBB2 protein, human
keywords: Advanced breast cancer; Bevacizumab; Capecitabine; First line; Taxane-free regimen; Vinorelbine