NE Oncology Issue – September 2012
Dang CT, et al. ASCO 2012: Abstract 532
Trastuzumab emtansine (T-DM1) has demonstrated clinical activity and favourable safety when used as a single agent in several studies of patients with metastatic breast cancer (MBC). As a result, there is considerable interest in exploring its use in patients with early-stage disease. However, monitoring the frequency and severity of cardiac dysfunction with the use of T-DM1 is of special interest given the cardiotoxicity associated with trastuzumab treatment and that women with early-stage breast cancer can expect long-term survival. At ASCO 2012, Dang and colleagues presented an assessment of the cardiac safety and clinical feasibility of T-DM1 following anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting for early-stage human epidermal growth factor receptor 2 (HER2)- positive breast cancer in this phase II study.1
- TDM4874g (NCT01196052) is a single-arm, openlabel, phase II study of T-DM1 in patients with early-stage HER2-positive breast cancer.
- Patients (N = 153) were enrolled in this study from October 2010 to June 2011.
- As of the clinical cut-off date, 148 patients had received at least one dose of T-DM1.
- A pre-chemotherapy left ventricular ejection fraction (LVEF) ≥55% by multigated acquisition (MUGA) scan/echocardiography (ECHO) was required for enrolment.
- Patients were administered one of two chemotherapy regimens:
- Doxorubicin (A)/cyclophosphamide (C)
- AC (A: 60 mg/m2; C: 600 mg/m2 once every two weeks [q2w] or q3w for four cycles); or
- 5-fluorouracil (F)/epirubicin (E)/cyclophosphamide (C)
- FEC (F: 500 mg/m2; E: 100 mg/m2; C: 600 mg/m2 q3w for three to four cycles).
- Doxorubicin (A)/cyclophosphamide (C)
- Followed by the HER2-directed agent:
- T-DM1 (3.6 mg/kg q3w intravenously [iv]; up to 17 cycles).
- The primary endpoints were safety and an allowable incidence rate of pre-specified cardiac events ≤6% following initiation of T-DM1 treatment.
- A pre-specified cardiac event was defined as death from a cardiac cause or severe congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) with a decrease in LVEF of ≥10 absolute percentage points from baseline to an LVEF <50%.
- The mean LVEF of patients (n = 147) pre-chemotherapy was 67.1% and changed very little over the course of treatment, although the values had greater variation approaching the end of treatment due to the fact that fewer patients had reached that point at clinical cut-off. (Figure 1)
- There were no symptomatic decreases in LVEF but 2.0% of patients experienced an asymptomatic decrease in LVEF. (Table 1)
- Neither pre-specified cardiac events nor T-DM1 discontinuations due to cardiac adverse events (AEs) had occurred at this time but 3.4% of patients experienced T-DM1–related cardiac AEs, such as atrial fibrillation, tricuspid valve incompetence, or palpitations.
- The most common all-grade T-DM1–related AEs were nausea, headache, epistaxis, asthenia, and pyrexia. (Table 2)
- Over one quarter of patients (26.4%) had grade 3 or 4 T-DM1–related AEs; no deaths occurred.
- The most common grade ≥3 AEs were thrombocytopenia, increased aspartate aminotransferase, and increased alanine aminotransferase.
- Some patients (3.4%) had T-DM1–related serious adverse events.
- Some patients (4.1%) experienced AEs leading to T-DM1 discontinuation.
- Early results indicate that T-DM1 following anthracycline-based chemotherapy was not associated with cardiac toxicity in patients with early-stage HER2-positive breast cancer.
Reference: 1. Dang CT, Gianni L, Romieu G, et al. Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as adjuvant or neoadjuvant therapy for early-stage HER2- positive breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts) 2012;(Suppl):532.
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.
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.
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.
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.
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.
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.
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.
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.