title: Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study.
abstract: OBJECTIVE
  To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC).
  
  
  METHODS
  In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5 mg/kg (day 1), docetaxel 50 mg/m(2) (day 1), oxaliplatin 100 mg/m(2) (day 1), capecitabine 850 mg/m(2) b.i.d. (days 1-14), and trastuzumab 6 mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6 months (observed in the ToGA trial) determined according to the lower limit of the 95 % confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS).
  
  
  RESULTS
  Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17 months, median PFS was 10.8 months (95%CI: 9.0-NA), OS was 17.9 months (95%CI: 12.4-NA). One-year PFS and OS were 52 % and 79 %, respectively. The ORR was 74 % (95%CI: 52-90 %). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related grade ≥ 3 adverse events were: neutropenia (16 %), diarrhoea (16 %), and hypertension (16 %).
  
  
  CONCLUSIONS
  B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC.
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Department of Oncology, St. Elisabeth Hospital, Tilburg, The Netherlands.
authors.forename: Laurens V
authors.initials: LV
authors.lastname: Beerepoot
authors.affiliation: Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Boot
authors.affiliation: Department of Medical Oncology, Isala, Zwolle, The Netherlands.
authors.forename: Jan Willem B
authors.initials: JW
authors.lastname: de Groot
authors.affiliation: Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Los
authors.affiliation: Department of Pathology, Isala, Zwolle, The Netherlands.
authors.forename: James E
authors.initials: JE
authors.lastname: Boers
authors.affiliation: Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Steven A L W
authors.initials: SA
authors.lastname: Vanhoutvin
authors.affiliation: Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands.
authors.forename: Marco B
authors.initials: MB
authors.lastname: Polee
authors.affiliation: Department of Internal Medicine, Spaarne Hospital Hoofddorp, Hoofddorp, The Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Beeker
authors.affiliation: Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands.
authors.forename: Johanna E A
authors.initials: JE
authors.lastname: Portielje
authors.affiliation: Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands.
authors.forename: Robert S
authors.initials: RS
authors.lastname: de Jong
authors.affiliation: Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands.
authors.forename: Swan H
authors.initials: SH
authors.lastname: Goey
authors.affiliation: Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Kuiper
authors.affiliation: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Karolina
authors.initials: K
authors.lastname: Sikorska
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Margot E
authors.initials: ME
authors.lastname: Tesselaar
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. a.cats@nki.nl.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D000068258:Bevacizumab / Q000008:administration & dosage; D000069287:Capecitabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D000077143:Docetaxel; D004943:Esophagogastric Junction / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000068258:Bevacizumab; D000069287:Capecitabine; D000077143:Docetaxel; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Adenocarcinoma; Bevacizumab; Gastric cancer; HER2; Stomach; Trastuzumab