NE Oncology Issue – April 2013

Metastatic Breast Cancer

In the HER2-positive metastatic breast cancer setting, clinical oncologists now have several anti-HER2 targeted agents at their disposal in addition to currently approved therapies such as trastuzumab and lapatinib. For example, trastuzumab emtansine (T-DM1), an antibody drug conjugate that links a monoclonal antibody, trastuzumab, to a potent antimicrotubule agent, DM1, through a stable linker, MCC, is selectively delivered to and subsequently released within HER2-positive breast cancer cells.1 Another example is pertuzumab, an anti-HER2 humanized monoclonal antibody that binds to a different epitope than trastuzumab on the HER2 receptor, which is the first in a new class of drugs known as HER2 dimerization inhibitors.2

In the HER2-positive early breast cancer (EBC) setting, one year of adjuvant trastuzumab therapy remains the standard of care based on the results of a number of trials. Also, the trial of a subcutaneous (sc) formulation of trastuzumab has aimed to make the delivery of this drug more efficient while maintaining its efficacy as a neoadjuvant or adjuvant therapy for HER2-positive EBC.

The latest results from clinical trials of HER2-directed therapies for breast cancer were presented at the European Society for Medical Oncology (ESMO) 2012 Congress and at the 2012 San Antonio Breast Cancer Symposium (SABCS).

In the HER2-positive metastatic breast cancer setting:

  • A second and confirmatory analysis of overall survival (OS) from the EMILIA study confirmed that T-DM1 provided a significant benefit in survival compared with capecitabine and lapatinib in patients with advanced breast cancer.
  • A pooled safety analysis from all trials of T-DM1 showed that it has limited systemic toxicity.
  • After longer follow-up, a second and confirmatory OS analysis of CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) confirmed the benefit of pertuzumab compared with placebo when used in combination with trastuzumab and docetaxel in patients with HER2-positive first-line metastatic breast cancer.
  • Analyses of patient samples from the CLEOPATRA study confirmed that HER2 was the only reliable marker for selecting patients for HER2-targeted therapy, but phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3), catalytic subunit alpha mutations may identify a poor prognostic group within the HER2-positive population that could be appropriate for clinical trials of HER2-targeted molecules in combination with PI3K pathway-targeted agents.

In the HER2-positive early breast cancer setting:

  • At a median eight years of follow up, the HERA trial showed no significant survival advantage for two years vs. one year of trastuzumab after adjuvant chemotherapy, but reconfirmed the beneficial efficacy and safety profile of one year of adjuvant trastuzumab with a statistically significant DFS and OS benefit versus chemotherapy alone after longterm follow-up.
  • The noninferiority of six vs. 12 months of adjuvant trastuzumab in early breast cancer could not be demonstrated in the PHARE trial.
  • The final planned joint analysis of OS from the National Surgical Adjuvant Breast and Bowel Project-31 and North Central Cancer Treatment Group N9831 trials showed that adding trastuzumab to adjuvant chemotherapy in a concurrent regimen benefited all patients, regardless of disease characteristics, by significantly improving DFS and OS after long-term follow-up.
  • In the HannaH study, the sc fixed-dose formulation of trastuzumab was just as efficacious across patient subgroups, had similar safety, and did not increase immunogenicity compared with the registered intravenous formulation.
  • The correlation of immune-related biomarkers with pathologic complete response from the NeoSphere trial of neoadjuvant pertuzumab (with or without trastuzumab and with or without docetaxel) confirmed that adaptive immune mechanisms seem to modulate the benefit from HER2-directed therapies.

References: 1. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res 2011;17:6437–47. 2. Keating GM. Pertuzumab in the first-line treatment of HER2-positive metastatic breast cancer. Drugs 2012;72:353–60.

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Canadian Perspectives

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Jean-Francois Larouche, MD

Dr. Jean-Francois Larouche obtained his medical degree in 2000. Upon graduation, he trained in internal medicine, hematology, and oncology at Laval University, Quebec City. Pursuing his interest in oncology, Dr. Larouche completed a postdoctoral fellowship in 2008 in Lyon, France, on lymphoma management. His interests include lymphomas and clinical research.

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Stephen Couban, MD, FRCPC

Dr. Stephen Couban is a professor of medicine at Dalhousie University and Director of the Blood and Marrow Transplant Program at Capital District Health Authority in Halifax, Nova Scotia. He is Co-Chair of the NCIC CTG Hematology Site Group and is also active with the Canadian Blood and Marrow Transplant Group. Dr. Couban is Vice President of the Canadian Hematology Society and a past-president of the Canadian Blood and Marrow Transplant Group. His research interests have focused on allografting and in particular on exploration of different types of grafts, including GCSF-stimulated allogeneic peripheral blood allografts and GCSF-stimulated bone marrow allografts. He is actively involved in a number of clinical trials for patients with leukemia and lymphoma, as well as those undergoing blood and marrow transplantation.

Investigator Commentary

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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 investigator 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, Lancet Oncology, Lancet, and The New England Journal of Medicine.

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Véronique Leblond, MD

Dr. Véronique Leblond is the Head of the Department of Haematology at Pitié- Salpêtrière Hospital, Paris, France. She has a long-standing research interest in the treatment of chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia (WM). Dr. Leblond has been the Principal Investigator of several multicentre trials investigating immunological therapies and novel chemotherapies. Currently, she is Chair of the French cooperative groups on CLL and WM, and is a member of the French Society of Haematology and the American Society of Haematology. Dr. Leblond has authored over 250 research articles, books, and book chapters.

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Francesco Lo-Coco, MD

Dr. Francesco Lo-Coco is a full Professor of Hematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biopathology, University of Rome Tor Vergata, Rome, Italy. His main research activities include genetic characterization, monitoring, and treatment of hematologic tumours, particularly acute myeloid leukemia and acute promyelocytic leukemia (APL). He has served as President of the Italian Society of Experimental Hematology, been a board member of the Italian Foundation for Cancer Research, and a member of the Committee on Health Research at the Italian Ministry of Health. He is presently chairman of the APL subcommittee of the Italian National Cooperative Group GIMEMA, chairman of the Education Committee of the European Hematology Association, and a member of the editorial board for the journals Leukemia and Haematologica.