Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study Gunter von Minckwitz, Andreas du Bois, Marcus Schmidt, Nicolai Maass, Tanja Cufer, Felix E. de Jongh, Eduard Maartense, Christoph Zielinski, Manfred Kaufmann, Wolfgang Bauer, Klaus H. Baumann, Michael R. Clemens, Ralph Duerr, Christoph Uleer, Michael Andersson, Robert C. Stein, Valentina Nekljudova, and Sibylle Loibl From the GBG Forschungs GmbH, Neu-Isenburg; Dr.-Horst-Schmidt- Kliniken, Breast Unit, Wiesbaden; University Women’s Hospital, Mainz; University Women’s Hospital, Kiel; Uni- versity Women’s Hospital, Frankfurt/ Main; Schwarzwald-Baar Klinikum, Villingen-Schwenningen; University Women’s Hospital, Marburg; Klinikum Mutterhaus der Borromaeerinnen, Trier; Klinikum Deggendorf; and Gemein- schaftspraxis Papcke/Uleer, Hildesheim, Germany; Institute of Oncology, Ljubljana, Slovenia; Ikazia Ziekenhuis, Rotterdam; and Reinier de Graaf Gast- huis, Delft, the Netherlands; Clinical Divi- sion of Oncology, Department of Medicine I, Medical University Vienna and Central European Cooperative Oncol- ogy Group, Vienna, Austria; Rigshospita- let University Hospital, Copenhagen, Denmark; and University College London Hospitals, London, United Kingdom. Submitted August 15, 2008; accepted December 9, 2008; published online ahead of print at www.jco.org on March 16, 2009. Supported by Roche AG, Germany, and by the University College London Hospitals/University College London (UCLH/UCL) Comprehensive Biomedical Research Centre (R.C.S.). Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Gunter von Minckwitz, MD, PhD, GBG Forschungs GmbH, University of Frankfurt, Schle- ussnerstr 42, Neu-Isenburg, Germany 63263; e-mail: Gunter.vonMinckwitz@ germanbreastgroup.de. The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®). © 2009 by American Society of Clinical Oncology 0732-183X/09/2712-1999/$20.00 DOI: 10.1200/JCO.2008.19.6618 A B S T R A C T Purpose Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)–positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Methods Patients with HER-2–positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m 2 body-surface area on days 1 through 14 [1,250 mg/m 2 semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. Results We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus- trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Conclusion Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2– positive breast cancer who experienced progression during trastuzumab treatment. J Clin Oncol 27:1999-2006. © 2009 by American Society of Clinical Oncology INTRODUCTION Change of treatment at disease progression is a general principle in oncology. It is not known whether this holds true for novel biologic agents like trastuzumab (Herceptin; Roche, Grenzach- Wyhlen, Germany), a humanized monoclonal antibody against the extracellular domain of hu- man epidermal growth factor receptor type 2 (HER-2, also referred to as HER-2/neu or ErbB- 2). Preclinical data indicate that trastuzumab is effective against tumor cell proliferation as long as it is present, whereas trastuzumab withdrawal re- sults in rapid tumor cell regrowth. 1,2 In addition, trastuzumab significantly enhances the antitumor effect of taxanes in tumors that progress with trastuzumab alone. 3 Clinical evidence on treatment with trastu- zumab beyond progression either alone or with a switch to a different chemotherapy is based, so far, on various retrospective analyses. 4-7 However, these results might be biased as a result of unknown fac- tors that influence physicians’ decisions to stop or to continue trastuzumab. Attempts in the United States (ie, at The M. D. Anderson Cancer Center and South West Oncology Group) with vinorelbine and JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 27  NUMBER 12  APRIL 20 2009 © 2009 by American Society of Clinical Oncology 1999 Downloaded from ascopubs.org by 54.242.233.114 on June 13, 2022 from 054.242.233.114 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.