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Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study

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Summary

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/m2 (day 1), oxaliplatin 100 mg/m2 (day 1), capecitabine 850 mg/m2 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.

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Acknowledgments

We thank the patients who participated in this study and their families. We are very grateful to the participating centres and the contribution of all study coordinators, nurse practitioners, and data managers who helped performing this study. This study was funded with an unrestricted grant from Hoffmann-La Roche.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Didier Meulendijks & Jan H. M. Schellens

  2. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Didier Meulendijks & Jan H. M. Schellens

  3. Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Didier Meulendijks, Henk Boot, Steven A. L. W. Vanhoutvin, Maria Kuiper & Annemieke Cats

  4. Department of Oncology, St. Elisabeth Hospital, Tilburg, The Netherlands

    Laurens V. Beerepoot

  5. Department of Medical Oncology, Isala, Zwolle, The Netherlands

    Jan Willem B. de Groot

  6. Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands

    Maartje Los

  7. Department of Pathology, Isala, Zwolle, The Netherlands

    James E. Boers

  8. Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands

    Marco B. Polee

  9. Department of Internal Medicine, Spaarne Hospital Hoofddorp, Hoofddorp, The Netherlands

    Aart Beeker

  10. Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands

    Johanna E. A. Portielje

  11. Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands

    Robert S. de Jong

  12. Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands

    Swan H. Goey

  13. Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Karolina Sikorska

  14. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jos H. Beijnen

  15. Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

  16. Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Margot E. Tesselaar

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  1. Didier Meulendijks
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Corresponding author

Correspondence to Annemieke Cats.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

This study was funded with an unrestricted grant from Hoffmann-La Roche. Author JWBG received personal fees from Hoffmann-La Roche.

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Meulendijks, D., Beerepoot, L.V., Boot, H. et al. Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study. Invest New Drugs 34, 119–128 (2016). https://doi.org/10.1007/s10637-015-0309-4

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