NE Oncology Issue – April 2013

New Evidence asked Dr. Sunil Verma, medical oncologist at the Sunnybrook Odette Cancer Centre, Associate Professor at the University of Toronto, and lead author of the recently published EMILIA trial,1 for his insights on the latest results from this study, which he presented at the ESMO 2012 Congress.

New Evidence: What is trastuzumab emtansine (T-DM1) and what are its advantages in the treatment of breast cancer?

Dr. Verma: T-DM1 is an antibody-drug conjugate that consists of trastuzumab bound through a stable linker to the chemotherapeutic agent, derivative of maytansine (DM1). DM1 is a potent antimicrotubule agent with a similar mechanism of action to vinca alkaloids. In preclinical studies, T-DM1 was found to be up to 200 to 500 times more potent than paclitaxel. There are several advantages offered by T-DM1 over trastuzumab alone. First of all, T-DM1 retains the intrinsic antitumour properties of trastuzumab, such as antibody-dependent cellular cytotoxicity. Secondly, the antibody portion of T-DM1 acts as a vehicle for the delivery of DM1 into cancer cells that overexpress human epidermal growth factor receptor 2 (HER2). Finally, T-DM1’s ability to precisely deliver chemotherapy to cancer cells leads to greater efficacy and less toxicity in the patient by reducing exposure of normal healthy cells to the drug.

New Evidence: How was the EMILIA trial designed to study T-DM1?

Dr. Verma: We enrolled patients with unresectable, locally advanced or metastatic breast cancer centrally confirmed as HER2-positive who had received prior therapy with a taxane and trastuzumab. Patients who had adjuvant trastuzumab and progressed within six months of completion of therapy were also eligible for inclusion in this trial. Those who fit the criteria were randomized in a 1:1 ratio to receive either T-DM1 intravenously at 3.6 mg/kg once every three weeks or capecitabine and lapatinib as per the standard dosing schedule.

New Evidence: What were the major clinical characteristics for patients in this trial?

Dr. Verma: In terms of previous treatments, nearly 100% of patients in EMILIA had received trastuzumab and a taxane. In addition, roughly 61% of patients had received prior anthracyclines and 40% had undergone endocrine therapy. For 12% of patients, the study drugs were the first line of therapy for metastatic breast cancer (MBC). The rest of the patients were receiving the drugs as a second, third, or even greater line of therapy. Approximately two thirds of patients had visceral disease and about one third of patients had three or more sites of metastases.

New Evidence: Was the patient population studied in EMILIA truly representative of your clinical practice?

Dr. Verma: The diversity of patients with HER2-positive breast cancer that I treat in the clinic was represented in EMILIA. The key to the trial’s design lay in the fact that it was not restricted to a particular line of therapy and that is more indicative of what happens on a daily basis in the clinical setting. As long as patients had received prior therapy with trastuzumab and a taxane, they were eligible for entry into this trial.

New Evidence: What are the treatment goals for patients with HER2-positive MBC in your clinical practice?

Dr. Verma: Our main goals are to decrease the patient’s symptom burden, to improve quality of life (QoL), to improve and control their disease for a greater period of time, and to improve survival. At the same time, we are trying as much as possible to help our patients live a normal life.

New Evidence: Please describe the hierarchy for the statistical analysis of endpoints in the EMILIA trial.

Dr. Verma: In addition to safety as a primary endpoint, the EMILIA trial was statistically designed to evaluate two independently assessed coprimary endpoints, progression-free survival (PFS) and overall survival (OS). The coprimary endpoints were organized into a hierarchy. We first assessed PFS and if the difference between treatment arms was significant, only then could we assess OS. If the difference in OS was also significant, then other key secondary endpoints could be assessed for significance.

New Evidence: What new efficacy data did you present at the ESMO 2012 Congress and how does it relate to the data presented at ASCO 2012?

Dr. Verma: At the ASCO 2012 annual meeting, we reported that T-DM1 provided a significant incremental improvement in PFS of 3.2 months compared with capecitabine and lapatinib. Although this improvement in PFS triggered assessment of OS, the results from our analysis did not quite cross the efficacy stopping boundary. Based on discussions with health authorities, we decided to conduct a second interim OS analysis once 50% of targeted OS events had taken place. The data cut-off point for our second analysis of OS was reached on July 31, 2012. At a median follow-up of 19 months in both treatment arms, OS with capecitabine and lapatinib was 25.1 months compared with 30.9 months for T-DM1, a difference of 5.8 months. The improvement in OS for patients in the T-DM1 arm was considered statistically significant at a hazard ratio (HR) = 0.68, p = 0.0006 and crossed the efficacy stopping boundary (HR = 0.72). Patients in the comparator arm are now able to cross over to T-DM1 making any further OS analysis purely descriptive.

New Evidence: What are your impressions of the safety data for T-DM1 compared with capecitabine and lapatinib in this trial?

Dr. Verma: The overall profile and rates of toxicities clearly favoured the T-DM1 arm, as there were fewer serious adverse events (AEs) and grade >3 AEs. We did need to monitor certain T-DM1-associated toxicities, such as thrombocytopenia and increased levels in liver function tests, and some patients required an appropriate dose modification. However, the toxicities associated with T-DM1 were much more manageable than those associated with capecitabine and lapatinib. As a result, patients in the T-DM1 arm were able to stay on therapy for a longer period of time leading to lower rates of treatment discontinuation.

New Evidence: Could you give us an overview of the findings from the QoL data in this trial?

Dr. Verma: T-DM1 clearly had superior efficacy and decreased toxicity and that was also captured in the QoL data, called patient-reported outcomes. One of the key secondary endpoint measures was the time to symptom progression, in which we collected the patient’s ratings of symptoms throughout the trial. The time to symptom progression was significantly delayed in the T-DM1 arm and was indicative of what we saw in the clinic. Patients receiving T-DM1 tolerated it much better and derived a greater benefit from it than the comparator regimen, thus providing the patient with a better QoL.

New Evidence: How do you foresee T-DM1 affecting patients with HER2-positive MBC in the clinical setting?

Dr. Verma: As per our study protocol, patients with advanced breast cancer who have previously received trastuzumab and a taxane will benefit from T-DM1. Based on our data, T-DM1 is superior to capecitabine and lapatinib. However, whether T-DM1 is superior or not to trastuzumab and chemotherapy is currently being studied. I would speculate that it will at least be on par with this regimen.

New Evidence: In addition to EMILIA, there are positive data from the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial for another HER2-targeted antibody, pertuzumab. Can you discuss how both T-DM1 and pertuzumab might be sequenced in lines of treatment for HER2-positive MBC?

Dr. Verma: There is no question that the administration of pertuzumab with trastuzumab and docetaxel is superior to trastuzumab and docetaxel alone, having improved PFS by a median of six months. However, the data we currently have for pertuzumab are limited to its administration with docetaxel, and so not all patients would be candidates to receive this chemotherapy. If pertuzumab were available, I would definitely consider using it along with trastuzumab and docetaxel as a first-line option for patients with a significant burden of disease where a quick response is needed. Upon progression, I would consider the use of either T-DM1 or trastuzumab and a chemotherapeutic agent. I would also consider using T-DM1 in earlier lines of therapy for those patients without a significant burden of disease who also meet the criteria for EMILIA, as long as there was funding and it was appropriately indicated on the label.

New Evidence: Are there any ongoing clinical trials to test the efficacy and safety of using T-DM1 in earlier stages of HER2-positive breast cancer?

Dr. Verma: In the first-line setting there is the MARIANNE trial, a three-armed study of T-DM1 plus pertuzumab versus T-DM1 versus trastuzumab plus docetaxel. We expect the results from this trial in the next two years. That will further guide us as to what is the best first-line treatment option for these patients and inform us on how well T-DM1 works in combination with pertuzumab. There is also great interest in evaluating pertuzumab in the adjuvant setting, which is being investigated in the APHINITY (Adjuvant Pertuzumab and Herceptin In Initial Therapy of Breast Cancer) trial. Trials are also planned for T-DM1 in the adjuvant setting.

New Evidence: How do the impressive results for T-DM1 in the EMILIA trial compare with past successes in the history of breast cancer clinical trials?

Dr. Verma: The magnitude of a 5.8-month increase in OS for T-DM1 compared with capecitabine and lapatinib is one of the largest ever recorded in breast cancer clinical trials to date. At times, I think we have become accustomed to seeing new anticancer agents make improvements in OS at the cost of increased toxicity. The truly remarkable aspects of the EMILIA trial are that T-DM1 has made one of the largest improvements in OS for patients with breast cancer and with fewer and less significant AEs compared with standard therapy. This is the kind of evidence that makes further development of the antibody-drug conjugate concept so very appealing to researchers and patients alike.

Reference: Verma S, Miles D, Gianni L, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med 2012. DOI: 10.1056/NEJMoa1209124.

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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.