NE Oncology Issue – September 2012

Following the ASCO 2012 annual meeting, New Evidence spoke with Dr. Kimberly Blackwell, Professor of Medicine and Assistant Professor of Radiation Oncology at Duke University Medical Center in Durham, North Carolina. She is also the Director of the Breast Cancer Program at Duke Cancer Institute and the lead author of the EMILIA study.

By Ben Fuerth

New Evidence: What outcomes are sought for patients who are being treated for metastatic breast cancer (MBC)?

Dr. Blackwell: When considering outcomes for patients who are being treated for MBC, we are not only thinking about length of life but also quality of life (QoL). It is a balance between keeping the breast cancer under control with treatment and not hurting the patient. We are moving beyond the old days of cancer care when the patient had to get really sick first, from the associated toxicities of treatment, in order to live longer. This new approach to care is slowly becoming a reality for the treatment of breast cancer and, for all practical purposes, other solid tumours as well.

New Evidence: What factors should be considered when selecting treatment for these patients?

Dr. Blackwell: There is still a real art to treating patients who are facing breast cancer. Even though we have many published treatment guidelines and approvals by regulatory bodies, such as the U.S. Food and Drug Administration, that drive our decision-making, we recognize that they are all built on population-based studies. The challenge is to take these population-based results and apply them to each individual patient sitting in our clinics. When I started treating patients with MBC 15 years ago, we had no human epidermal growth factor receptor 2 (HER2)-targeted treatment options. By the end of 2012, we will hopefully have four HER2-targeted agents — trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) — to pick and choose from, thus allowing us to achieve that therapeutic balance for each individual patient. Treatment-related decisions are made not only by talking to the patient about the data as they relate to large populations of women, but also by considering what is important to the patient, known as patient-assigned goals.

New Evidence: What is trastuzumab resistance and how significant a problem is it when treating patients with breast cancer?

Dr. Blackwell: Trastuzumab resistance in the treatment of breast cancer is quite difficult to define. Until we have a better understanding of the biology and more precise sequential biopsy samples from patients who progress or relapse after receiving trastuzumab, I do not think we will have a good idea. Right now, our clinical practice is driven by the agents that patients have received and not necessarily by how well they will work. I am not sure that we can call it trastuzumab resistance if patients relapse locally or in the brain two years after receiving a year of trastuzumab treatment. It may just be that we should have kept on administering trastuzumab or that the treatment prevented the cancer from returning everywhere else but the brain. For now, we will just have to do the best we can in the clinic to figure out which treatments work and have a good understanding of the patient populations being accrued in clinical trials before widely using new drugs.

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

Dr. Blackwell: In the EMILIA study, we chose lapatinib and capecitabine as the control arm because the indication for their use is in patients who have progressed on trastuzumab and taxane-based chemotherapy. Consequently, this combination was thought to be an appropriate first-, second-, or third-line therapy for patients with MBC. The experimental arm included the use of only one drug, T-DM1. Since T-DM1 retains all of the properties of its parent antibody, trastuzumab, it made more sense to use a comparator that was already considered a very active agent in these patients. We wanted to include a broad range of patients by enrolling some who had received no prior treatment for MBC to, in this case, a third of our patients who had already received up to two years of treatment. The two main endpoints of this study were progression-free survival (PFS) and overall survival (OS). For the purpose of developing a less toxic therapy, this study also performed an extensive assessment of the patient’s QoL. It was well recognized that although lapatinib and capecitabine form an active combination, the combination is also associated with a lot of toxic side effects, in particular, diarrhea, rash, nausea, and vomiting. In terms of QoL, the other important consideration was comparing T-DM1, which is given intravenously once every three weeks, to the orally administered, daily pills regimen of lapatinib and capecitabine.

New Evidence: Please describe the unique mechanism of action employed by the new antibody-drug conjugate technology in T-DM1.

Dr. Blackwell: One of the most exciting aspects of the EMILIA study was that it provided the first proof-of-concept of an antibody-drug conjugate for the treatment of a solid tumour. These antibody-drug conjugates have been the holy grail of cancer therapy. That is to say, if we could design a drug that would only target the cancer cells and not the host’s cells, we could make something really toxic to the tumour while having minimal impact on the patient. T-DM1 was designed to do exactly that because it is composed of a chemotherapeutic agent, DM1, bound to an antibody, trastuzumab, which targets the overexpressed HER2 receptor on breast cancer cells. In the wake of the results from EMILIA, the antibody-drug conjugate concept has received a lot of attention because it could have widespread applicability for the treatment of many other diseases beyond solid tumours. It took close to two decades of research to understand how to properly bind a toxin to an antibody through a stable linker molecule such that the toxin would only be released within the target cell. In the case of T-DM1, it was the culmination of a lot of basic research in lysosomal biology. Now that we understand it, I believe the door has been swung wide open to the development of other antibody-drug conjugates.

New Evidence: How did the efficacy of T-DM1 compare with lapatinib and capecitabine in this trial?

Dr. Blackwell: The use of T-DM1 improved PFS by 3.6 months over lapatinib and capecitabine. This was a statistically significant result in which the study had met its endpoint, triggering an analysis of OS independent of how many deaths had actually occurred. At that point, median OS had not been reached for T-DM1 compared with 23.3 months in the control arm. The study narrowly missed the early overall efficacy stopping boundary for OS (hazard ratio [HR] = 0.617 or p = 0.0003) since the HR was 0.621 and the p-value was 0.0005. At the time of the analysis, there was an absolute difference of 18% in OS at the two-year mark. This is the largest difference we have ever seen in an MBC trial and with additional follow-up, we would expect the pre-defined OS endpoint to be met as well.

New Evidence: Why did T-DM1 provide a significant improvement in PFS for every patient subgroup analyzed except for those without visceral disease or those who were 65 years or older?

Dr. Blackwell: The simplest reason for not having seen as much of a beneficial effect with T-DM1 in patients without visceral disease is that the presence of visceral disease is easily measured whereas its complete absence is much more difficult to ascertain. We did allow for an evaluable disease in the study. For example, a patient could have had bone-only disease and a pleural effusion. About one third of patients in the study were classified as being without visceral disease. Typically, this means their disease is more difficult to measure, therefore, determining PFS in this subgroup may have been done with a little less precision. As far as elderly patients are concerned, they only constituted about one seventh of the total patient population. This was a much smaller subgroup, which is usually prone to more variability. When looking at the absolute difference in PFS between study arms for both of these subgroups, it certainly appears as though T-DM1 is favoured.

New Evidence: How did the safety profile of T-DM1 compare with lapatinib and capecitabine in this study?

Dr. Blackwell: The safety profile for T-DM1 certainly supported the idea that an antibody-drug conjugate can directly deliver chemotherapy while sparing normal tissues from toxicity. One of the measurements we look at is adverse events (AEs) leading to treatment discontinuation. The percentage of patients in the control arm (10.7%) who experienced these kinds of events was almost double that seen in patients in the experimental arm (5.9%) of this study. For lapatinib and capecitabine, treatment discontinuation can largely be attributed to an increase in diarrhea, hand-foot syndrome, vomiting, and nausea. T-DM1 occasionally produced elevations in alanine aminotransferase and aspartate aminotransferase that were typically asymptomatic and resolved once the drug was stopped. We also saw grade 4 thrombocytopenia in about 3% of patients who were given T-DM1. This strange occurrence, which was identified early on in drug development, needs to be monitored and is currently under investigation. In the clinic, the sequelae of AEs associated with lapatinib and capecitabine treatment have a greater impact on the patient’s QoL than some of these laboratory abnormalities seen with T-DM1. Time to symptom progression and scores on the Functional Assessment of Cancer Therapy-Breast scale both showed a significant delay in the worsening of the QoL for those patients in the T-DM1 arm.

New Evidence: What was the cardiac toxicity profile of T-DM1 in the EMILIA study?

Dr. Blackwell: Although it was quite a concern when trastuzumab showed early signs of increasing the incidence of cardiac events, we recognize now that these are fairly infrequent but still need to be monitored. In the control versus experimental arms of EMILIA, only 1.6% and 1.7% of patients, respectively, had a decline in their left ventricular ejection fraction. This indicates that even though the toxin is being delivered to cells expressing the HER2 protein, it does not appear to be reaching the myocardium. It is thought that T-DM1 only delivers the drug to cells that express at least two million copies of HER2 compared with normal cellular expression of approximately 10,000 copies of this protein. The reason for occasional incidents of cardiotoxicity with T-DM1 is still unknown but this drug does not appear to cause an increased signal over what is normally seen with trastuzumab alone.

New Evidence: Are there any disadvantages to T-DM1 compared with other therapies available?

Dr. Blackwell: Treatment with T-DM1 is just a 30-minute infusion, no pre-medications are required, and patients do not lose their hair. In fact, when some of my patients and I were interviewed by the press, we had a unique problem because everyone was worried about how their hair was going to look. It dawned on me that up until that point, none of the patients I had ever been interviewed with still had their own hair. The fact is the toxicity of T-DM1 is not something that the patient has to monitor because it can be tracked by laboratory values.

New Evidence: Will there still be a role for lapatinib and capecitabine in the treatment of HER2-positive MBC?

Dr. Blackwell: This goes back to the art of oncology but I think lapatinib remains an approved and active agent for patients with HER2-positive MBC. If T-DM1 is approved, I believe it will be a preferred agent but there is still a role for lapatinib in patients who have progressed on T-DM1. Lapatinib also remains the only HER2-targeted agent that is approved in combination with endocrine therapy. This is a patient population that is not typically treated with chemotherapy, thus lapatinib is still a viable option prior to receiving chemotherapy for MBC.

New Evidence: Considering the results from the EMILIA and Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trials, can you discuss how T-DM1 and pertuzumab might fit into clinical algorithms for the treatment of HER2-positive MBC?

Dr. Blackwell: It is important to point out that CLEOPATRA was a different kind of study than EMILIA. CLEOPATRA was conducted in patients with first-line MBC and roughly 80% of them had never received trastuzumab. This is in stark contrast to the EMILIA study where 100% of the patients had previously received trastuzumab, only to have disease progression or relapse. Although both agents were studied in the MBC domain, they should drive clinicians to utilize them in different settings. The CLEOPATRA study indicates that pertuzumab should be used in addition to trastuzumab and chemotherapy for patients who have not received trastuzumab, whereas the EMILIA study points to the use of T-DM1 over lapatinib in patients who have progressed after having previously received trastuzumab and a taxane. The logical progression would be to use pertuzumab and trastuzumab in the first-line metastatic setting and then to use T-DM1 once patients have already seen those agents. Currently, I am unaware of any clinical trials testing the efficacy and safety of administering T-DM1 in earlier stages of breast cancer, but there is obviously a lot of discussion about T-DM1 being used in the adjuvant setting. The priority trial right now is the Adjuvant Pertuzumab and Herceptin In Initial Therapy of Breast Cancer (APHINITY) trial, which is testing the addition of pertuzumab. However, T-DM1 could also be used for patients who have progressed following pertuzumab therapy in a study like APHINITY.

New Evidence: What are the clinical factors that drive these decisions?

Dr. Blackwell: As clinicians, we like to see evidence of efficacy and broad coverage of patient populations for new drugs. It should be stated that these drugs are going to be quite expensive, adding a significant cost to the treatment of HER2-positive MBC. Currently in my clinical practice, I will be limiting the use of both these drugs to the same patient populations in which they were tested. We should have the results soon from a phase III clinical trial called MARIANNE, which enrolled a patient population that is comparable to CLEOPATRA, comparing trastuzumab plus chemotherapy versus T-DM1 alone versus T-DM1 plus pertuzumab. The results from that trial will set the stage for how we should treat first-line MBC. Until then, I think pertuzumab and trastuzumab should be used first followed by T-DM1 in the metastatic setting.

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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.