Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer

  • Cristina Grávalos
  • Carlos Gómez-Martín
  • Fernando Rivera
  • Inmaculada Alés
  • Bernardo Queralt
  • Antonia Márquez
  • Ulpiano Jiménez
  • Vicente Alonso
  • Rocío García-Carbonero
  • Javier Sastre
  • Ramon Colomer
  • Hernán Cortés-Funes
  • Antonio Jimeno
Research Articles



HER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer.

Materials and methods

Chemo-naïve patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m2), both intravenously on day 1, every 21 days.


Twenty-two out of 228 patients (10%) were HER2-positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1–41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival.


Trastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers.


Gastric cancer Gastroesophageal junction adenocarcinoma HER2 Phase II Trastuzumab 


  1. 1.
    Kelley JR, Duggan JM (2003) Gastric cancer epidemiology and risk factors. J Clin Epidemiol 56:1–9PubMedCrossRefGoogle Scholar
  2. 2.
    Sastre J, García-Saenz JA, Díaz-Rubio E (2006) Chemotherapy for gastric cancer. World J Gastroenterol 12:2004–2213Google Scholar
  3. 3.
    Wagner AD, Grothe W, Haerting J et al (2006) Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 24:2903–2909PubMedCrossRefGoogle Scholar
  4. 4.
    Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRefGoogle Scholar
  5. 5.
    Kaptain S, Tan LK, Chen B (2001) Her-2/neu and breast cancer. Diagn Mol Pathol 10:139–152PubMedCrossRefGoogle Scholar
  6. 6.
    Yano T, Ochiai A, Doi T et al (2004) Expression of HER2 in gastric cancer: comparison between protein expression and gene amplification using a new commercial kit. J Clin Oncol 22:14S(Abstr 4053)Google Scholar
  7. 7.
    Park DI, Yun JW, Park JH et al (2006) HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 51:1371–1379PubMedCrossRefGoogle Scholar
  8. 8.
    Kang YK, Bang YJ, Lordick F et al (2008) Incidence of gastric or gastro-esophageal cancer in the ToGA trial: correlation with HER2 positivity. Gastrointestinal Cancers Symposium p. 75 (abstr 11)Google Scholar
  9. 9.
    Tokunaga A, Onda M, Okuda T et al (1995) Clinical significance of epidermal growth factor (EGF), EGF receptor and c-erbB-2 in human gastric cancer. Cancer 75:1418–1425PubMedCrossRefGoogle Scholar
  10. 10.
    Park DI, Yun JW, Park JH et al (2006) HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci 51:1371–1379PubMedCrossRefGoogle Scholar
  11. 11.
    Yonemura Y, Ninomiya I, Yamaguchi A et al (1991) Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short-term prognosis in gastric cancer. Cancer Res 51:1034–1038PubMedGoogle Scholar
  12. 12.
    Tanner M, Hollmen M, Junttila TT et al (2005) Amplification of HER-2 in gastric carcinoma: association with topoisomerase IIa gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 16:273–278PubMedCrossRefGoogle Scholar
  13. 13.
    Grávalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19:1523–1529PubMedCrossRefGoogle Scholar
  14. 14.
    Matsui Y, Inomata M, Tojigamori M et al (2005) Suppression of tumor growth in human gastric cancer with HER2 overexpression by an anti-HER2 antibody in a murine model. Int J Oncol 27:681–685PubMedGoogle Scholar
  15. 15.
    Fujimoto-Ouchi K, Sekiguchi F, Yasuno H et al (2007) Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol 59:795–805PubMedCrossRefGoogle Scholar
  16. 16.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10PubMedCrossRefGoogle Scholar
  17. 17.
    Ajani JA, Lee FC, Singh DA et al (2006) Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 24:663–667PubMedCrossRefGoogle Scholar
  18. 18.
    Ridwelski K, Gebauer T, Fahlke J et al (2001) Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer. Ann Oncol 12:47–51PubMedCrossRefGoogle Scholar
  19. 19.
    Roth AD, Maibach R, Martinelli G et al (2000) Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Res (SAKK), and the European Institute of Oncology (EIO). Ann Oncol 11:301–306Google Scholar
  20. 20.
    Ajani JA, Fodor MB, Tjulandin SA et al (2005) A multi-institutional phase II randomized trial of docetaxel plus cisplatin (DC) or DC plus 5-fluorouracil (DCF) in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol 23:5660–5667PubMedCrossRefGoogle Scholar
  21. 21.
    Van Cutsem E, Moiseyenko VM, Tjulandin S et al (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol 24:4991–4997PubMedCrossRefGoogle Scholar
  22. 22.
    Colomer R, Montero S, Lluch A et al (2000) Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 6:2356–2362PubMedGoogle Scholar
  23. 23.
    Fornier MN, Seidman AD, Schwartz MK et al (2006) Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate. Ann Oncol 16:234–239CrossRefGoogle Scholar
  24. 24.
    Bang YJ, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376(9742):687–697PubMedCrossRefGoogle Scholar
  25. 25.
    Nicholas G, Cripps C, Au H-P et al (2006) Early results of a trial of trastuzumab, cisplatin and docetaxel for the treatment of metastatic gastric cancer overexpressing HER-2. ESMO abstr 1105Google Scholar
  26. 26.
    Rech J, Arnold D, Folprecht G et al (2006) A pilot study of trastuzumab monotherapy in patients who progressed while on chemotherapy for metastatic or locally advanced HER-2 positive gastric cancer. ESMO abstr 1096Google Scholar

Copyright information

© Feseo 2011

Authors and Affiliations

  • Cristina Grávalos
    • 1
  • Carlos Gómez-Martín
    • 1
  • Fernando Rivera
    • 3
  • Inmaculada Alés
    • 4
  • Bernardo Queralt
    • 5
  • Antonia Márquez
    • 6
  • Ulpiano Jiménez
    • 7
  • Vicente Alonso
    • 8
  • Rocío García-Carbonero
    • 9
  • Javier Sastre
    • 10
  • Ramon Colomer
    • 11
  • Hernán Cortés-Funes
    • 1
  • Antonio Jimeno
    • 2
  1. 1.Medical Oncology DepartmentUniversity Hospital 12 de OctubreMadridSpain
  2. 2.University of Colorado Cancer CenterAuroraUSA
  3. 3.Medical Oncology DepartmentUniversity Hospital Marqués de ValdecillaSantanderSpain
  4. 4.Medical Oncology DepartmentHospital Carlos HayaMálagaSpain
  5. 5.Medical Oncology DepartmentHospital Josep TruetaGironaSpain
  6. 6.Medical Oncology DepartmentHospital Virgen de la VictoriaMálagaSpain
  7. 7.Medical Oncology DepartmentUniversity Hospital La PrincesaMadridSpain
  8. 8.Medical Oncology DepartmentHospital Miguel ServetZaragozaSpain
  9. 9.Medical Oncology UnitHospital Severo OchoaLeganés, MadridSpain
  10. 10.Medical Oncology DepartmentUniversity Hospital San CarlosMadridSpain
  11. 11.MD Anderson Cancer Center EspañaMadridSpain

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