Didier Meulendijks1,2,3, Laurens V Beerepoot4, Henk Boot3, Jan Willem B de Groot5, Maartje Los6, James E Boers7, Steven A L W Vanhoutvin3, Marco B Polee8, Aart Beeker9, Johanna E A Portielje10, Robert S de Jong11, Swan H Goey12, Maria Kuiper3, Karolina Sikorska13, Jos H Beijnen14,15, Margot E Tesselaar16, Jan H M Schellens1,2,15, Annemieke Cats17. 1. Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 2. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 3. Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. 4. Department of Oncology, St. Elisabeth Hospital, Tilburg, The Netherlands. 5. Department of Medical Oncology, Isala, Zwolle, The Netherlands. 6. Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands. 7. Department of Pathology, Isala, Zwolle, The Netherlands. 8. Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands. 9. Department of Internal Medicine, Spaarne Hospital Hoofddorp, Hoofddorp, The Netherlands. 10. Department of Medical Oncology, Haga Hospital, The Hague, The Netherlands. 11. Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands. 12. Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands. 13. Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 14. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 15. Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands. 16. Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 17. Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. a.cats@nki.nl.
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.
OBJECTIVE: To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced humanepidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). METHODS: In this multicentre, single-arm, phase II study, tumorHER2 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.
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