NE Oncology Issue – September 2012

Ewer M, et al. ASCO 2012: Abstract 533^

Background

In patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), therapy with anthracyclines, trastuzumab, and especially their concomitant administration, has been associated with cardiac dysfunction. Cardiotoxicity related to trastuzumab therapy is not well understood but, in contrast to anthracycline-induced cardiac injury, the majority of trastuzumab-related cardiac events are reversible after treatment discontinuation. Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA), a phase III trial, tested the safety and efficacy of combining docetaxel and trastuzumab with pertuzumab, a HER2 dimerization inhibitor with a distinct binding epitope, or placebo as a first-line therapy for patients with HER2-positive MBC. The addition of pertuzumab significantly improved progressionfree survival compared with placebo, from 12.4 to 18.5 months.1 At ASCO 2012, Ewer and colleagues presented their analysis of the CLEOPATRA study for cardiac tolerability of this novel treatment regimen.2

Study design

  • CLEOPATRA is a randomized, double-blind, placebocontrolled, phase III trial (NCT00567190).
  • Patients (n = 808) with centrally confirmed HER2- positive MBC were enrolled; 804 patients were included in the safety population.
  • Patients received one of two treatment regimens:
    • Pertuzumab plus trastuzumab and docetaxel (pertuzumab group); or
    • Placebo plus trastuzumab and docetaxel (placebo group).
  • Study drugs were administered intravenously once every three weeks until disease progression or unmanageable toxicity:
    • Pertuzumab/placebo: 840 mg initial dose, 420 mg subsequent doses;
    • Trastuzumab: 8 mg/kg initial dose, 6 mg/kg subsequent doses;
    • Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated (≥6 cycles recommended).
  • Inclusion criteria were a baseline left ventricular ejection fraction (LVEF) ≥50%, no history of congestive heart failure, and no LVEF decline to <50% during/after prior trastuzumab.
  • LVEF was assessed by echocardiography or multigated acquisition (MUGA) scanning at baseline, every nine weeks during treatment, at discontinuation, and up to three years thereafter.
  • Adverse events (AEs) were monitored continuously and graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0).
  • Symptomatic left ventricular systolic dysfunction (LVSD) was reported as a serious adverse event and graded according to the NCI-CTCAE v3.0 and New York Heart Association (NYHA) classifications.

Ewer-ASCO2012-study

Key findings

  • The incidence of any cardiac disorder (grade ≥1) as assessed by the investigators was similar for both groups: placebo group (16.4%) and pertuzumab group (14.5%).
  • Two patients in the placebo arm of the study died due to myocardial infarction.
  • LVSD grade ≥1 was the most frequent cardiac AE and more common in patients treated in the placebo group compared with the pertuzumab group (8.3% vs. 4.4%). (Table 1)
  • At the time of data cut-off for this analysis, eight of the 11 symptomatic LVSD events (seven events in the placebo group vs. four events in the pertuzumab group) had resolved; none were fatal.
  • All patients who developed symptomatic LVSD had one or more potential cardiac risk factors (prior exposure to anthracyclines, trastuzumab, and radiation, smoking, diabetes, hypertension, etc.). (Table 2)
  • Compared with the overall patient population, only prior anthracycline (hazard ratio [HR] = 2.21; 95% confidence interval [CI]: 1.27–3.86; p = 0.0053) and prior radiation (HR = 2.43; 95% CI 1.37–4.31; p = 0.0025) exposures were identified as potentially important risk factors in patients who developed symptomatic LVSD.
    • However, prior anthracycline and radiation exposures had no influence on the overall analysis of the time to first asymptomatic or symptomatic LVSD event.
  • LVEF decline to <50% and by ≥10% points from baseline was more frequent in the placebo group (6.6% vs. 3.8%), but most patients in both the placebo (72.0%) and pertuzumab (86.7%) groups recovered LVEF ≥50% on or after stopping treatment. (Table 3)

Key conclusion

  • CLEOPATRA provides evidence that pertuzumab, when combined with trastuzumab and docetaxel, does not increase the frequency of overall cardiac disorders compared with placebo.

Reference: 1. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366(2):109–119. 2. Ewer MS, Baselga J, Clark E, et al. Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in the CLEOPATRA study. J Clin Oncol (ASCO Annual Meeting Abstracts) 2012;(Suppl):533.

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Canadian Perspectives

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Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal inves - tigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, and Lancet Oncology.

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Douglas A. Stewart, BMSc, MD, FRCPC
Dr. Douglas A. Stewart is currently a pro - fessor in the Departments of Oncology and Medicine, and Chief of the Division of Hematology and Hematological Ma - lignancies at the University of Calgary. Since July 1994, he has been practising medical oncology at the Tom Baker Cancer Centre in Calgary, where he is a member of the Breast Cancer and Hematology Tumour Groups, Leader of the Hematology/Blood and Marrow Transplant Program, and Provincial Leader of the Hematology Tumour Team for the Alberta Health Services Cancer Care Program. His research interests focus on clinical trials involving hematological malignancies and hematopoietic stem cell transplantation. Dr. Stewart has authored over 80 peer-reviewed manuscripts and over 120 abstracts.

Investigator Commentaries

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Kimberly L. Blackwell, MD

Dr. Kimberly Blackwell is a medical oncologist, Professor of Medicine, and Assistant Professor of Radiation Oncology at Duke University Medical Center in Durham, North Carolina, U.S. She is the Director of the Breast Cancer Program at the Duke Cancer Institute and serves on the national Scientific Advisory Board of the Susan G. Komen for the Cure. She received her undergraduate degree in bioethics at Duke University, and her medical degree at Mayo Clinic Medical School. Afterwards, Dr. Blackwell completed an internal medicine internship and residency, and a hematology-oncology fellowship at Duke University Medical School. In addition to maintaining an active clinical practice, she has served as a principal investigator on many clinical trials in breast cancer. Her research interests include breast cancer angiogenesis, breast cancer in younger women, endocrine therapy, and HER2-targeted therapy. Dr. Blackwell has authored or co-authored over 40 articles or book chapters appearing in journals such as Clinical Cancer Research, the Journal of Clinical Oncology, Cancer, Radiation Research, and Molecular Cancer Therapeutics. In the past year, she has reviewed for several grant committees and peer-reviewed journals.

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Tony Mok, MD
Dr. Tony Mok studied medicine at the University of Alberta and subsequently completed his fellowship training at the Princess Margaret Hospital in Toronto. After practising oncology and internal medicine for seven years in Toronto, Dr. Mok became an Assistant Professor in the Department of Clinical Oncology at the Chinese University of Hong Kong in 1996. He became a full professor in 2007. He holds an honorary professorship at the Guangdong Provincial People’s Hospital in Guangdong, China, and a guest professorship at the Peking University School of Oncology. He is heavily involved in several professional societies and committees, including being President-elect of the International Association for the Study of Lung Cancer. Dr. Mok is the Associate Editor of several journals and has published over 130 articles in peer-reviewed journals.

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Mathias J. Rummel, MD, PhD
Mathias J. Rummel is the head of the Department for Hematology at the Clinic for Hematology and Medical Oncology at the Justus-Liebig University-Hospital, Giessen, Germany. Professor Rummel studied medicine at J.W. Goethe University Hospital in Frankfurt, Germany, obtaining his licence to practice medicine in 1995. Following this, he completed his doctoral degree and residency, obtained board certification in internal medicine, and was awarded his PhD from J.W. Goethe University Hospital. Professor Rummel’s current research focuses on novel treatment approaches in hematological malignancies, most notably follicular and other indolent lymphomas as well as hairy cell leukemia and also immune thrombocytopenic purpura (ITP). He is the chair of the Study group indolent Lymphomas (StiL) and principal investigator of several ongoing clinical trials in leukemias, lymphomas, and ITP. He is actively involved in a number of professional scientific societies, he is a reviewer for a number of journals, and has several published book chapters and papers to his credit.

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Barbara F. Eichhorst, MD
Dr. Eichhorst graduated from the University of Munich School of Medicine in 1997, having completed a doctoral thesis in the field of hematology that focused on evaluating the signal transduction pathways of Hodgkin cells. She became a consultant in internal medicine after finishing an internship at Klinikum Grosshadern in the Department of Internal Medicine III at the University of Munich. Shortly after its founding, Dr. Eichhorst became a leading member of the German CLL Study Group and has served as the group’s secretary since 2005. She has published several papers on the treatment of chronic lymphocytic leukemia (CLL) and has acted as principal investigator for several phase II and III clinical trials that evaluated treatment optimization in CLL. Dr. Eichhorst is currently an Associate Professor at the University of Cologne and a consultant in hematology and internal oncology at the University Hospital of Cologne.

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Arnon Nagler, MD, MSc
Arnon Nagler is Professor of Medicine at the Tel Aviv University, Tel Aviv, Israel, and the Director of both the Division of Hematology and the Bone Marrow Transplantation and Cord Blood Bank at the Chaim Sheba Medical Center, Tel Hashomer, Israel. Dr. Nagler received his medical training at the Hebrew University-Hadassah Medical School, Jerusalem, Israel, specializing in hematology at the Rambam Medical Center, Haifa, Israel. He carried out a postdoctoral research fellowship in hematology and bone marrow transplantation at Stanford University Hospital in Palo Alto, California, U.S. Dr. Nagler has been working in the fields of bone marrow transplantation for hematological malignancies, including non-Hodgkin lymphoma, and hemato-oncology, for the last 20 years. In Israel, Dr. Nagler established the first public cord blood bank and performed the first cord blood transplantations from related and unrelated donors in genetic and malignant hematological disease. His main clinical interests include stem cells, bone marrow transplantation, hematological malignancies, cord blood biology, and adoptive cell-mediated immunotherapy. Dr. Nagler has written numerous articles, reviews, and chapters for peer-reviewed journals, and is the principal investigator for a number of clinical studies. He serves on the Editorial Board of several journals and is a Section Editor for Leukemia.

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Michael Hallek, MD
Dr. Michael Hallek is Professor of Medicine, and Director and Chair of the Department of Internal Medicine I at the University of Cologne in Cologne, Germany, where he oversees internal medicine, hematology, hemostaseology, oncology, intensive care, infectious diseases, and immunology. From 1994–2005, Dr. Hallek was head of the Gene Therapy Program at the Gene Center of the University of Munich and of the Clinical Cooperation Group for Gene Therapy at the National Centre for Research on Environment and Health (GSF) in Munich. In 2007, Dr. Hallek was appointed Director of the Center of Integrated Oncology (CIO), the joint comprehensive cancer centre of the Universities of Cologne and Bonn. Since 1994, he has been Chair of the German CLL Study Group. Dr. Hallek is the principal investigator for the CLL-8 clinical trial.