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Background

Capecitabine vs. capecitabine + trastuzumab in patients with HER-2 positive metastatic breast cancer progressing during trastuzumab treatment – the TBP phase III study (GBG 26 / BIG 3-05).

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Background

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  1. Capecitabine vs. capecitabine + trastuzumab in patients with HER-2 positive metastatic breast cancer progressing during trastuzumab treatment – the TBP phase III study (GBG 26 / BIG 3-05) von Minckwitz G, Zielinski C, Maartense E, duBois A, Schmidt M, Maass N, Cufer T, De Jongh FE, Andersson M, Stein R, Kaufmann M, Nekljudova V, Loibl S On behalf of German Breast Group and AGO; CECOG; BOOG; Slovenia; DBG; CR-UK; BIG

  2. Background Way of action of trastuzumab is poorly understood. Antibody-dependent cellular cytotoxicity (ADCC) might be predominant mechanism [1] Retrospective studies suggest that continuation of trastuzumab beyond progression is beneficial [2]. Prospective approaches failed so far. Prospective study proved lapatinib + capecitabine to be superior to capecitabine alone in patients who progressed on trastuzumab [3] 1. Barok M et al, Mol Cancer Ther 2007; 2. Tripathy D et al. J Clin Oncol 2004; 3. Geyer et al. N Engl J Med 2006.

  3. Study Design of GBG 26 X: Capecitabine 2500 mg/m² d 1 – 14 q 22 R XH: Capecitabine 2500 mg/m² d 1 – 14 q 22 and continuation of Trastuzumab 6 mg/kg q22

  4. Objectives of GBG 26 Primary objective: Time to progression Secondary objectives: Safety Objective response Clinical benefit Overall survival

  5. Eligibility and Sample Size HER2 positive, locally advanced / metastatic breast cancer Disease progression during trastuzumab treatment No more than 1 palliative chemotherapy LVEF ≥ 50% 482 pts to show improvement by continuing trastuzumab from 4 to 5.1 months (ß=80%, α=5%, one-sided p significance)

  6. Results 156 pts recruited between 01/04 - 05/07 Recruitment stopped after FDA registration of lapatinib on advice of IDMC Pre-treatment : Taxane / trastuzumab as 1st-line therapy (N=111) Trastuzumab alone or with other 1st line CT (N=42) Taxane / trastuzumab as adjuvant treatment (N=3)

  7. Patient Characteristics

  8. Hematological Toxicities P=0.02 * Not significant, if not indicated

  9. Non-Hematological Toxicities * Not significant, if not indicated

  10. Cardiac and Fatal Toxicities 1 Patient showed decrease of LVEF < 40 during XH 2 (2.7%) pts with X and 4 (5.2%) pts with XH showed other grade 3 cardiac events Hypertension (2), suspected MI (1), LVEF decrease (1), pericardial effusion (1), general cardiac complaint (1) No therapy related death was observed

  11. Clinical Response (RECIST) OR: 27.0% CB: 54.1% OR: 48.0% CB: 75.3% OR: 0.0115 CB: 0.0068 (2-sided p) CR: 7.7% CR: 2.7% PR: 40.4% PR: 24.3% NC: 27.1% NC: 27.2% OR = Overall response = CR+PR CB = Clinical benefit = CR+PR+NC>24wks

  12. Time To Progression • X : 5.6 (4.2 - 6.3) mos • XH : 8.2 (7.3 - 11.2) mos • HR=0.69 (two-sided p=0.034; one-sided p=0.017) P<0.0467 Progression to CNS: X: 8.3% XH: 13.8% PFS X: 5.6 mos XH: 8.2 mos P=0.026 two sided median follow-up: 15.6 mos

  13. Overall Survival • X : 20.4 (17.8 – 24.7) mos • XH : 25.5 (19.0 – 30.7) mos • HR=0.76 (two-sided p=0.26; one-sided p=0.13)

  14. Conclusions of GBG 26 Continuing trastuzumab beyond progression improves efficacy of 2nd line capecitabine treatment in HER2-positive metastatic breast cancer patients in terms of: Response rate (48.0 vs. 27.0%; p=0.01) Clinical benefit rate (75.3 vs 54%; p=0.007) Time to progression (8.2 vs 5.6 mos; p=0.034) Progression-free survival (8.2 vs 5.6 mos; p=0.026) Overall survival (25.5 vs 20.4 mos; non sign. trend) No increase in toxicity

  15. Acknowledgements • All patients • All investigators • All collaborative groups: AGO; CECOG; BOOG; Slovenia; DBG; CR-UK; BIG • Staff at GBG headquarter • Roche AG Germany for financial support and drug supply

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