NE Oncology Issue – September 2012

Robidoux A, et al. ASCO 2012: Abstract LBA506

Background

The standard neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer is administration of doxorubicin and cyclophosphamide combined with weekly paclitaxel and trastuzumab leading up to surgery.1 Lapatinib, combined with a cytotoxic agent, is used to treat patients with metastatic breast cancer (MBC) whose tumours have progressed on trastuzumab.2 Even though lapatinib and trastuzumab are both HER2-directed agents, they operate through different mechanisms of action and can have synergistic activity.3 The authors of this phase III clinical trial attempted to determine whether substitution of or addition to the HER2-targeted component of standard neoadjuvant therapy, trastuzumab, with lapatinib might improve outcomes for patients with HER2-positive operable breast cancer.4

Study design

  • This interventional trial was a multicentre, international, randomized, open-label, phase III design (NCT00486668).
  • Patients (N = 529) were accrued for the trial from July 2007 to June 2011.
  • Inclusion criteria for patients in this study were a palpable tumour ≥2 cm, diagnosis by core needle biopsy, left ventricular ejection fraction ≥50%, and confirmation of a HER2-positive tumour.
  • All patients received part of the standard neoadjuvant treatment regimen. It consisted of doxorubicin and cyclophosphamide followed by weekly paclitaxel, combined with trastuzumab, lapatinib, or both trastuzumab and lapatinib.
  • The study drugs were administered as follows:
    • Doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 intravenously (iv) every 21 days for cycles 1–4);
    • Weekly paclitaxel (80 mg/m2 iv on days 1, 8, and 15 every 28 days for cycles 5–8).
  • While taking weekly paclitaxel, patients were also administered the HER2-targeted agents:
    • Trastuzumab: 4 mg/kg iv initial dose, 2 mg/kg iv subsequent dose weekly until one week before surgery;
    • Lapatinib: 1,250 mg orally each day until one day before surgery;
    • Trastuzumab plus lapatinib: trastuzumab (same dosage) and lapatinib (750 mg orally each day until one day before surgery).
  • The primary endpoint was pathologic complete response (pCR) in the breast.
  • Secondary outcome measures were complete clinical response (cCR), pCR in the breast and negative nodes, and toxicities (cardiac and non-cardiac).

Robidoux-ASCO2012-study

Key findings

  • The percentage of patients who fully completed the protocoldefined neoadjuvant therapies was significantly different between the treatment groups (trastuzumab = 78%, lapatinib = 68%, trastuzumab plus lapatinib = 63%; p = 0.01).
    • However, the percentage of patients who at least started the fourth cycle of HER2-directed treatment was not significantly different between groups (trastuzumab = 82%, lapatinib = 73%, trastuzumab plus lapatinib = 72%; p = 0.082).
  • The percentage of patients reaching a cCR decreased when they were treated with lapatinib compared with trastuzumab (69.9% vs. 82%, p = 0.014).
  • The combination of trastuzumab plus lapatinib compared with trastuzumab (76.8% vs. 82.0%, p = 0.3) did not confer any difference in the percentage of patients with a cCR. (Figure 1)
  • Lapatinib or trastuzumab plus lapatinib neoadjuvant therapies compared with the standard of trastuzumab did not significantly change the percentage of patients achieving a pCR in the breast (lapatinib vs. trastuzumab: 53.2% vs. 52.5%, p = 0.99; trastuzumab plus lapatinib vs. trastuzumab: 62% vs. 52.5%; p = 0.095). (Figure 2)
  • When the treatment groups were divided by hormone receptor status (positive or negative) and compared, there was no difference in the percentage of patients achieving a pCR in the breast. (Figure 3)
  • The percentage of patients with a pCR in the breast and negative nodes remained unchanged in the trastuzumab vs. lapatinib groups (49.4% vs. 47.4%) and was marginally increased in the trastuzumab plus lapatinib group vs. trastuzumab alone (60.2% vs. 49.4%, p = 0.056). (Figure 4)
  • Dividing the treatment groups into two categories of HER2 expression levels by immunohistochemistry (IHC), IHC low (0+, 1+, and 2+) and IHC 3+, revealed that a greater percentage of patients with IHC 3+ levels of HER2 attained a pCR when treated with trastuzumab plus lapatinib compared with trastuzumab (71% vs. 54.7%; p = 0.006). (Figure 5)
  • An interaction of pCR with IHC levels was detected in the trastuzumab plus lapatinib vs. trastuzumab groups (p = 0.021).
  • Overall grade ≥3 adverse events (AEs), more specifically grade 3 diarrhea (trastuzumab = 2%, lapatinib = 20%, trastuzumab plus lapatinib = 27%; p <0.001), occurred with greater frequency in patients from both of the lapatinibtreated groups compared with trastuzumab.
  • Differences in the percentage of patients experiencing febrile neutropenia, hepatic toxicity, or congestive heart failure between treatment arms were not significant.

Key conclusions

  • Substitution of lapatinib for trastuzumab in neoadjuvant therapy for operable breast cancer was equally as efficacious as trastuzumab in nearly every outcome measure except for cCR.
  • The combination of the two HER2-directed agents, trastuzumab and lapatinib, may be more effective than trastuzumab alone as a neoadjuvant therapy for patients with operable breast cancer that express high levels of HER2 protein.
  • The main difference in AEs was an increased frequency of diarrhea for both of the lapatinibcontaining treatment regimens compared with the standard trastuzumab regimen.

Reference: 1. NCCN Guidelines for Patients: Breast Cancer, Version 2.2011. National Comprehensive Cancer Network. http://www.nccn.com/files/cancerguidelines/ breast/index.html. Accessed June 14, 2012. 2. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):2733–2743. 3. O’Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol (ASCO Annual Meeting Abstracts) 2008;26:1015. 4. Robidoux A, Tang G, Rastogi P, et al. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. J Clin Oncol (ASCO Annual Meeting Abstracts) 2012;(Suppl):LBA506.

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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.