NE Oncology Issue – June 2007

Background

By binding to HER2 protein receptors, trastuzumab interrupts the growth signal, thereby slowing the growth and spread of breast cancer cells. In this way, trastuzumab, a monoclonal antibody, targets breast cancer cells that over-express the HER2 protein. A pivotal study by Dennis Slamon and colleagues compared chemotherapy alone versus chemotherapy plus trastuzumab.1 This study demonstrated that the addition of trastuzumab to chemotherapy, either doxorubicin/cyclophosphamide (AC) or paclitaxel, improved response rate, time to progression, median survival, and one-year survival rate. The improvement in survival was seen in spite of the 65% of women in the control arm who ultimately received trastuzumab. Since that study, multiple chemotherapy regimens have been tested in combination with trastuzumab. Treatment with paclitaxel, docetaxel, a taxane plus a platinum salt, or vinorelbine plus trastuzumab are all trastuzumab-containing regimens in the metastatic breast cancer setting.

The Breast Cancer International Research Group (BCIRG) presented the results of BCIRG-007 at ASCO in 2006.2 This study compared docetaxel plus trastuzumab (TH) versus the triplet carboplatin plus docetaxel plus trastuzumab (TCH) in the first-line treatment of metastatic breast cancer. The dose of docetaxel was 100 mg/m2 in the TH arm compared with 75 mg/m2 in the TCH arm. There was no difference in response rate (TH 72.5% versus TCH 72.7%) or time to progression (TH 11 months versus TCH 10.3 months) across the two arms. Both regimens would appear to be acceptable, and the study raised important questions about the role of a platinum salt in combination with a taxane in the treatment of HER2-positive metastatic breast cancer. At ASCO 2007, the first overall survival analysis of the BCIRG-007 trial was presented.3

Study design

  • The BCIRG-007 trial enrolled 263 women with fluorescence in situ hybridization–confirmed, HER2-positive metastatic breast cancer (Table 1).
  • Median follow-up was 39 months.
  • The primary endpoint of the study is time to disease progression (TTP).
  • Secondary endpoints include
    • Response rate (RR), duration of overall response (OR), and clinical benefit
    • Toxicity
    • Overall survival
    • Pathologic and molecular markers
  • No crossover was allowed between arms.
  • The power of the trial was set to 80%, to detect a 50% improvement in median TTP.
  • The number of events required for final analysis was set at 204 (significance = 0.05, power = 0.8).

asco07-4-study-lrg

Key findings

  • After 39 months of follow-up, there was no difference in the survival rate of either the TH or TCH arms (39.1 months versus 39.2 months, p = 0.65).
  • Grade 3 and 4 toxicities occurred with similar frequency in both treatment arms, with the exception of thrombocytopenia, nausea, and emesis, which were more common with the carboplatin-containing regimen (Table 2 and 3).
  • All grade sensory neuropathy, rash, myalgia, and nail changes were significantly more common in the trastuzumab plus docetaxel arm compared with the carboplatin-containing arm (Table 3).
  • More patients given TCH received the maximum number of chemotherapy cycles (79% versus 64%).

Key conclusions

  • The addition of carboplatin to the docetaxel and trastuzumab combination failed to improve outcomes from docetaxel plus trastuzumab alone.
  • There are no statistical differences in response rate, time to progression, or survival between the two treatments, though the study was underpowered to detect modest differences.
  • Both therapies effectively treat HER2-positive metastatic breast cancer, with a time to progression of greater then 10 months and an overall survival of more than 36 months.
  • There was more grade 3 or 4 thrombocytopenia, nausea, and emesis in the carboplatin-containing arm.
  • Myalgia, rash, and nail changes were more common with the docetaxel-trastuzumab regimen.
  • Because of the asymmetry in the docetaxel doses (TH 100 mg/m2 versus TCH 75 mg/m2), it cannot be ruled out that carboplatin played a role in the response in the lower-dose docetaxel arm.

References: 1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783–792. 2. Forbes JF, Pienkowski T, Valero V, et al. BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC). 2006 ASCO Annual Meeting Proceedings J Clin Oncol 2006;24(18S):LBA516. 3. Pegram M, Forbes JF, Pienkowski T, et al. First overall survival analysis of a multicenter phase III randomized trial comparing docetaxel and trastuzumab as first line chemotherapy for patients with metastatic breast cancer containing the HER2/neu alteration. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1–5, 2007; Chicago, Illinois; Abstract LBA1008.

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Contributors

dr-hirsh
Vera Hirsh, MD, FRCPC
Chief of the Hematology-Oncology Service, Santa Cabrini Hospital
Associate Professor, Medicine and Oncology, McGill University
Associate Physician, Oncology Service, at the Royal Victoria, Montreal General, and Montreal Chest Hospitals
With a current practice in both hematology and oncology, Dr. Vera Hirsh is an associate professor of medicine and oncology at McGill University. Her research at the Quebec Pulmonary Unit focuses on the treatment of lung cancer, and she continues to chair ongoing international chemotherapy trials. Dr. Hirsh chaired the Quebec Lung Cancer Committee to establish guidelines for the treatment of lung cancer. In addition, she has published abstracts, articles, and book chapters. Dr. Hirsh is a member of advisory boards for many pharmaceutical companies and the Medical Oncology Standing Committee of RTOG.

dr-cripps
Christine Cripps, MD, FRCPC
Medical Oncologist, Director,
Continuing Medical Education,
Ottawa Hospital Regional Cancer Centre
Dr. Christine Cripps is a medical oncologist and director of the Continuing Medical Education Department at the Ottawa Hospital Regional Cancer Centre. She also holds a position of Associate Professor, Medicine at the University of Ottawa. A keen teacher, Dr. Cripps’ main areas of interest include gastrointestinal cancer and head and neck cancer. She also enjoys cycling, skiing, and sailing when time permits.

dr-chia
Stephen K. L. Chia, MD, FRCPC
Assistant Professor of Medicine Department of Medicine
University of British Columbia
British Columbia Cancer Agency
Dr. Chia is a staff oncologist with the British Columbia Cancer Agency (BCCA), Vancouver, Canada. He also serves as physician coordinator for both the breast cancer and head and neck cancer clinical trials at the BCCA – Vancouver Cancer Centre. He is an active researcher in phase I-III trials in breast cancer, head and neck cancer and investigational new drugs. He is currently carrying out studies in breast cancer with grant funded research from the National Cancer Institute of Canada, Canadian Breast Cancer Alliance and Canadian Breast Cancer Foundation – British Columbia/Yukon Chapter. Dr. Chia is an active member of the British Columbia Breast Tumor Group, Breast Cancer Systemic Policy Group and Head and Neck Tumor Group.

dr-chang
José Chang, MD, FRCPC
Head of Medical Oncology, RS
McLaughlin Durham Regional Cancer Centre, Oshawa
Dr. José Chang is the principal investigator and site representative for the National Cancer Institute of Canada Clinical Trials Group, and is an examiner for the Medical Council of Canada. His research interests lie in the areas of breast cancer, melanoma, lymphoma, and quality of life during chemotherapy. Dr Chang has presented at major oncology meetings of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposia, and European Breast Cancer Conference. A member of the editorial board of the journal Current Oncology, Dr. Chang has published in journals such as the Journal of Clinical Oncology, European Journal of Cancer, and Canadian Medical Association Journal.