NE Oncology Issue – September 2012

Gelmon KA, et al. ASCO 2012: Abstract LBA671


Lapatinib, an orally active, reversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, is approved for use in combination with capecitabine as therapy for patients who have received prior treatment for HER2-positive locally advanced (LABC) or metastatic breast cancer (MBC). As a firstline therapy for patients with HER2-positive MBC, lapatinib has been shown to improve efficacy over placebo when used in combination with paclitaxel. This trial, presented by Gelmon and colleagues at the ASCO 2012 meeting, was designed to directly compare the efficacy and safety of a first-line therapy using lapatinib or trastuzumab in combination with taxane-based chemotherapy for patients with HER2-positive MBC.1

Study design

  • This was a multicentre, international, open-label, randomized, phase III clinical trial (NCIC CTG MA.31, NCT00667251).
  • Patients (N = 636) with MBC and no prior chemotherapy or HER2-targeted therapy for MBC were randomized and treated in this trial.
  • Patients received either:
    • Lapatinib with a taxane, followed by lapatinib monotherapy (LTax/L);
    • Trastuzumab with a taxane followed by trastuzumab monotherapy (TTax/T).
  • The dosages of study drugs administered for the first 24 weeks of therapy were a taxane:
    • Paclitaxel: 80 mg/m2 intravenously (iv) weekly for the first three weeks, then once every four weeks for six courses;
    • Docetaxel: 75 mg/m2 iv on day 1, then once every three weeks (q3w) for eight courses (plus granulocyte colony-stimulating factor prophylaxis for patients taking lapatinib).
    • In combination with a HER2-directed agent:
      • Lapatinib: 1,250 mg orally each day;
      • Trastuzumab: 4 mg/kg iv initial dose, then 2 mg/kg iv weekly or 8 mg/kg iv initial dose, then 6 mg/kg iv q3w.
  • Following the first 24 weeks of treatment, patients received monotherapy with the HER2-directed agent, lapatinib (1,500 mg orally each day) or trastuzumab (6 mg/kg iv q3w), corresponding to their initial therapy for four years or until progressive disease (PD).
  • The primary endpoint of this study was progression-free survival (PFS) as determined by Response Evaluation Criteria In Solid Tumors 1.0 or death from any cause and analyzed by intent to treat (ITT).
  • A secondary analysis of PFS was performed with patients who had centrally confirmed HER2- positive tumours.
  • The secondary endpoints of this study were overall survival (OS) and safety.
  • Further analyses will include treatment exposure, incidence of and time to central nervous system (CNS) metastases, response rates, among others but were not reported at this presentation.

Gelmon-ASCO 2012-study

Key findings

  • After median follow-up times of 12.9 months in the lapatinib arm and 14 months in the trastuzumab arm, ITT analysis indicated that the median time of PFS in the LTax/L arm (8.8 months [95% confidence interval (CI): 8.3–10.6]) was inferior compared with the TTax/T arm (11.4 months [95% CI: 10.8–13.7]), hazard ratio (HR) = 1.33 (95% CI: 1.06-1.67); p = 0.01. (Figure 1)
  • The secondary analysis of PFS, which only included patients with centrally-confirmed HER2-positive tumours, also showed that LTax/L was inferior to TTax/T (9.0 vs. 13.7 median months, HR = 1.48 [95% CI: 1.15–1.92]; p = 0.003).
  • No difference in OS was detected between the treatment arms when comparing LTax/L with TTax/T, regardless of whether it was analyzed by ITT (HR = 1.1 [95% CI: 0.75– 1.61]; p = 0.62) or by HER2-positive status (HR = 1.25 [95% CI: 0.81–1.93]; p = 0.32). (Figure 2)
  • Safety data profiles differed between the two treatment arms:
    • Overall, more serious adverse events (SAEs) were reported in the LTax/L group (136 vs. 78), with a greater number of cases of diarrhea (32 vs. 5).
    • A higher frequency of two grade ≥3 adverse events (AEs), diarrhea (19.3% vs. 1.3%) and rash (8.9% vs. 0.3%), occurred in patients taking LTax/L.
    • A greater percentage of patients treated with TTax/T experienced a decrease ≥20% of LVEF from baseline over the course of the study. (Table 1)
    • A total of 10 deaths on treatment took place in the TTax/T arm compared with five deaths in the LTax/L arm.

Key conclusions

  • Patients receiving TTax/T compared with LTax/L had a statistically significant increase in PFS, as indicated by median differences of 2.6 months for the ITT population and 4.7 months in those with centrally confirmed HER2-positive tumours.
  • The two therapies produced different safety data profiles with diarrhea and rash occurring more frequently with LTax/L while a greater percentage of TTax/T patients experienced a ≥20% decrease in LVEF.

Reference: 1. Gelmon KA, Boyle F, Kaufman B, et al. Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919. J Clin Oncol (ASCO Annual Meeting Abstracts) 2012;(Suppl):LBA671.

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Canadian Perspectives


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.

Investigator Commentaries


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.