NE Oncology Issue – September 2012

Following the ASCO 2012 annual meeting, New Evidence asked Dr. Sunil Verma, medical oncologist at the Sunnybrook Odette Cancer Centre and Associate Professor at the University of Toronto, for his perspective on some of the breast cancer clinical trials that were presented. He is the senior author of the EMILIA trial.

New Evidence: What is known about the mechanism for trastuzumab resistance in breast cancer?

Dr. Verma: Our understanding of resistance to trastuzumab-based therapy is limited because patients tend to respond even after disease progression. There may be an expression of p95, a truncated HER2 receptor. There may also be a role for MUC4, an extracellular protein that could inhibit trastuzumab from binding to the human epidermal growth factor receptor 2 (HER2). There are also some downstream resistance pathways, such as upregulation of the mTOR and PI3K-Akt pathways, which the immune modulatory effects of trastuzumab may be unable to overcome. We are continually addressing how to treat these patients through clinical trials with new agents and combination therapies, but there is no prototype of trastuzumab-resistant breast cancer that can be properly examined. Therefore, trastuzumab resistance remains an ill-defined term. All we can say is that these patients, even after disease progression, continue to derive some benefit from HER2-targeted therapy with either trastuzumab or lapatinib.

New Evidence: How is lapatinib used in your clinical practice?

Dr. Verma: We use lapatinib as a second- or third-line therapy for our patients who have had up to one or two lines of previous trastuzumab-based therapy in the metastatic setting. For patients who have progressed on taxanes and trastuzumab, lapatinib has shown to be effective when given in combination with capecitabine. The challenge with capecitabine and lapatinib is the associated toxicity profile because patients have higher rates of grade 3/4 diarrhea and rash. Lapatinib is also effective when given in combination with letrozole for hormone receptor-positive, HER2-positive breast cancer and in combination with trastuzumab as a totally targeted combination approach.

New Evidence: What was the rationale for the EMILIA trial?

Dr. Verma: Our standard approach to treatment for patients whose breast cancer has progressed on taxanes and trastuzumab in the metastatic setting includes capecitabine and lapatinib. At times, we may consider using other chemotherapies with trastuzumab instead to treat these patients. In previous phase II trials, a new drug called trastuzumab emtansine (T-DM1) has shown response rates of approximately 30% to 40% for patients with HER2-positive metastatic breast cancer (MBC). T-DM1 is an antibody-drug conjugate that is composed of the antibody, trastuzumab, linked to DM1, a potent cytotoxic microtubule inhibitor, through a stable linker molecule. In the EMILIA trial, we wanted to see how effective and safe T-DM1 was compared with the standard treatment of capecitabine and lapatinib in a randomized, phase III trial.

New Evidence: What are your impressions of the efficacy data and safety profile for T-DM1 in the EMILIA trial?

Dr. Verma: The results of the EMILIA trial show that T-DM1 is a game changer. It is more effective than capecitabine and lapatinib in terms of prolonging progression-free survival (PFS) and it shows a trend towards improving overall survival (OS). T-DM1 also has fewer serious side effects than standard treatment, which can improve the quality of life for patients with MBC. Many of the side effects that our patients find debilitating were not seen in those treated with T-DM1. For example, we did not see any hair loss, febrile neutropenia, or infections. About 5% of patients did develop grade 3/4 transaminitis — elevations in their liver enzymes — and there was an approximately 15% rate of grade 3/4 thrombocytopenia, but the risk of significant bleeding was quite low.

New Evidence: How does T-DM1 compare with trastuzumab in terms of the risk for cardiotoxicity?

Dr. Verma: Most of the concerns in the past over increased cardiotoxicity with trastuzumab have been in the context of patients who were previously treated with anthracyclines or when trastuzumab was administered in close proximity with anthracyclines. Previous phase II trials for T-DM1 have indicated that there is no clear increase in cardiotoxicity with this agent. There were some data presented at the ASCO meeting from the TDM4874g phase II trial that showed T-DM1 had a manageable cardiac safety profile, even after anthracycline treatment. The authors of this study examined the use of T-DM1 following anthracycline-based chemotherapy for patients with breast cancer in either the adjuvant or neoadjuvant settings. They found very little change in patients’ mean left ventricular ejection fraction over the course of treatment and few cardiac adverse events, none of them leading to treatment discontinuation at the time of analysis. The cardiac safety data for T-DM1 from EMILIA, in which cardiotoxicity was one of the secondary endpoints, also showed that there were no increased rates of cardiac adverse events over the standard treatment of capecitabine and lapatinib. However, in terms of the full cardiotoxic profile for T-DM1, we still need to study the drug further, including more studies in the early-stage breast cancer setting, to see how it compares with a taxane plus trastuzumab.

New Evidence: Which patients would benefit most from this new antibody-drug conjugate T-DM1?

Dr. Verma: The eligibility criteria in the EMILIA study were for patients who had progressed on treatment with a taxane and trastuzumab. Therefore, if it is approved, treatment with T-DM1 would be appropriate for patients who have progressed on those treatments, either taxanes in the adjuvant setting or trastuzumab in the adjuvant and metastatic settings. This antibody-drug conjugate, T-DM1, allows us to deliver targeted therapy without significant side effects that would impact the patient’s quality of life. The reason for this is that chemotherapy is directed right to the cancer cell without exposing normal tissues to as much of the cytotoxic agent, essentially decreasing the amount of free drug exposure to the patient. This form of precision chemotherapy allows for greater efficacy without significant toxicity. It is the first in class for such an approach in solid tumours and will offer patients with HER2-positive MBC a therapy that is well-tolerated and efficacious.

New Evidence: What was the rationale for the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study?

Dr. Verma: The CLEOPATRA study was designed to evaluate whether we can improve on the efficacy seen with the standard treatment of a taxane plus trastuzumab for patients with HER2-positive MBC. The treatment for the control arm of this study was docetaxel plus trastuzumab plus a placebo and the experimental arm was docetaxel plus trastuzumab plus pertuzumab. Pertuzumab is a monoclonal antibody that prevents the dimerization of HER2 and HER3 and it appears to be synergistic with trastuzumab. The question to be answered was can we combine the two HER2-directed agents with a chemotherapy backbone of a taxane for the treatment of patients in the first-line metastatic setting as part of a randomized, phase III trial.

New Evidence: What are your impressions of the cardiac safety of pertuzumab in this trial?

Dr. Verma: The results for the CLEOPATRA study, first presented in San Antonio, were very impressive. There was an improvement in PFS from 12.5 months with docetaxel and trastuzumab to about 18 months when pertuzumab was added to the combination. The data on cardiac safety suggest that the addition of pertuzumab, while increasing efficacy, does not increase the cardiac toxicity over taxanes and trastuzumab.

New Evidence: What are the advantages of combining two HER2-targeted agents over administering just one for the treatment of HER2-positive MBC?

Dr. Verma: The reason for combining two different HER2-targeted agents as a treatment approach is that complete blockade of the HER2 receptor is needed. Trastuzumab alone does not block the potent dimerization of HER2 and HER3, which leads to an increased signal transduction cascade and aggressiveness of the breast cancer. Pertuzumab on its own is not that efficacious but the synergy of both agents is clearly showing greater efficacy over trastuzumab alone. Blocking this receptor dimerization is clinically important and the data showing extended PFS are evidence of that. We have some data that indicate the combination of trastuzumab with lapatinib is also very effective but the lapatinib toxicity profile limits its ability to be combined with chemotherapy. This also makes it difficult to study as a combination therapy. There are not many phase III trials studying the combination of trastuzumab and lapatinib with chemotherapy and I think these are still needed.

New Evidence: Is pertuzumab available in Canada and how would you use this new drug in your clinical practice?

Dr. Verma: Pertuzumab, recently approved by the U.S. Food and Drug Administration, is not available at this time in Canada because it is currently going through the Health Canada review process. However, we do have clinical studies, which will be opening soon, to evaluate this drug in the metastatic setting and to see if benefit will transfer to the adjuvant setting. The trial in the adjuvant setting, called Adjuvant Pertuzumab and Herceptin In Initial Therapy of Breast Cancer (APHINITY), will be opening in a number of centres across the country. As long as pertuzumab is approved, funded, and available, I think this will be the new standard treatment approach for patients in the first-line setting. The one challenge with pertuzumab is that the current level of evidence for its safety and efficacy is solely based upon its combination with docetaxel. I think that may limit our use of this drug to a certain degree but results from future studies will address whether or not we can change the chemotherapy backbone. There are studies ongoing to see whether we can combine pertuzumab with paclitaxel, other taxanes, and other chemotherapies like vinorelbine.

New Evidence: What other breast cancer trial results presented at ASCO 2012 could have a significant impact on clinical practice in Canada?

Dr. Verma: In terms of HER2-positive breast cancer, there were a couple of other key presentations, one of which looked at a taxane with lapatinib versus a taxane with trastuzumab. This was the MA31 clinical trial presented by Dr. Karen Gelmon. The authors showed that a taxane plus trastuzumab was superior to a taxane plus lapatinib in prolonging PFS, but there was no significant difference in OS between the treatment arms. This trial was really informative and solidifies the idea that trastuzumab may be better than lapatinib in the first-line, metastatic setting.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 trial, presented by Dr. André Robidoux, examined the combination of weekly paclitaxel with lapatinib, trastuzumab, or both drugs following the standard treatment of doxorubicin and cyclophosphamide in the neoadjuvant setting. The authors found that lapatinib and trastuzumab were equally effective but the toxicity profile favoured the trastuzumab arm. Similar to previously reported neoadjuvant studies, the combination of lapatininb and trastuzumab was superior to the single HER2-targeted strategy.

Another metastatic breast cancer trial, the Cancer and Leukemia Group B (CALGB) study, looked at ixabepilone versus weekly paclitaxel versus weekly nanoparticle albumin-bound (nab)-paclitaxel. It showed that weekly paclitaxel was superior to ixabepilone and may be just as good as weekly nab-paclitaxel. The challenge in that study was that 98% of the patients received bevacizumab, so the interpretation of the study is somewhat diluted by this fact. However, there was no incremental benefit of nab-paclitaxel over paclitaxel, so this is also a significant study result that may have an impact on clinical practice.

New Evidence: What is the biggest challenge that Canadian oncologists face when treating breast cancer?

Dr. Verma: The biggest challenge that Canadian oncologists face is related to the cost of the drugs because, even though the benefit that we are seeing is quite significant, the cost of paying for such therapies can also be significant. We do need to ensure that we are utilizing these treatments in an evidence-based manner. We also need to assess the patient’s receptor status with a biopsy of metastatic disease upon relapse because that really guides us in our ability to give the appropriate therapy. That being said, I do think Canadian oncologists should be very proud because we are offering the best possible treatments to our patients. Many of the studies that were presented at ASCO had a Canadian impact. For instance, I am the senior author on the EMILIA study. Dr. Karen Gelmon, from the British Columbia Cancer Agency, is the first author on the MA31 clinical trial. In addition, Dr. André Robidoux, from the Breast Cancer Research Centre at l’Université de Montréal, is the first author on the NSABP B-41 study. This year’s ASCO annual meeting certainly had a true Canadian flavour.

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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.