NE Oncology Issue – April 2013

Verma S, et al. ESMO 2012:LBA12

Background

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab bound through a stable linker to the antimicrotubule agent DM1. The EMILIA trial, recently published in the New England Journal of Medicine,1 was designed to compare the safety and efficacy of T-DM1 with capecitabine and lapatinib for treating patients with human epidermal growth factor receptor 2 (HER2)-positive unresectable locally advanced or metastatic breast cancer. The first interim overall survival (OS) analysis showed a strong trend favouring T-DM1, but it narrowly missed crossing the efficacy stopping boundary so a second interim OS analysis was performed. The results from this final analysis were presented at the ESMO 2012 Congress by Dr. Sunil Verma and colleagues.2

Study design

  • EMILIA is a multicentre, international, randomized, open-label, two-arm, phase III clinical trial (NCT00829166).
  • Patients (N = 991) with centrally confirmed HER2- positive locally advanced or metastatic breast cancer were randomized in a 1:1 ratio and treated with T-DM1 or lapatinib in combination with capecitabine.
  • Patients eligible for enrolment had tumours that had either progressed while receiving treatment for metastatic disease or recurred within six months of completing adjuvant trastuzumab, and had received a prior taxane and trastuzumab but no prior capecitabine or lapatinib.
  • Patient demographics and baseline characteristics were evenly balanced between study arms.
  • Patients received one of the following regimens until disease progression or unmanageable toxicity:
    • T-DM1 (n = 495) at a dosage of 3.6 mg/kg intravenously once every three weeks (q3w);
    • Capecitabine and lapatinib (n = 496) at the respective dosages for capecitabine (1,000 mg/m2 orally twice a day, on days 1–14 q3w) and lapatinib (1,250 mg orally each day).
  • The primary end points were progression-free survival (PFS) assessed by an independent review committee, OS, and safety.
  • The secondary end points included PFS assessed by the investigator, objective response (OR) rate, duration of response (DR) and time to symptom progression.
  • Hierarchical statistical analysis of end points was performed in the following prespecified sequential order: PFS by independent review followed by OS and then secondary end points.
  • The final analysis of PFS and first interim OS analysis were based on the data cut-off of January 14, 2012.
  • The data cut-off for the second interim OS analysis was July 31, 2012, once 50% of targeted OS events had occurred.

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Key findings

  • The final analysis of PFS by independent review showed that T-DM1 significantly prolonged PFS by 3.2 months compared with capecitabine and lapatinib (9.6 vs. 6.4 median months, HR = 0.650 [95% CI]: 0.55–0.77; p <0.0001).
  • The benefit in PFS of T-DM1 over capecitabine and lapatinib was consistently observed across clinically relevant subgroups, with a less definitive benefit among patients 75 years of age or older and those with nonvisceral disease.
  • The earlier trend for OS favouring T-DM1 was confirmed by the second interim OS analysis, as the median OS for patients in the T-DM1 arm was 5.8 months longer compared with the capecitabine and lapatinib arm (30.9 months vs. 25.1 months). (Figure 1)
  • The difference in OS between the two study arms was now considered significant (HR = 0.682 [95% CI: 0.55–0.85]; p = 0.0006) since it crossed the efficacy stopping boundary (HR = 0.727 or p = 0.0037). This is now considered the final OS analysis and any further analysis will be strictly descriptive. (Figure 1)
  • At one year and two years post-treatment, OS rates were also in favour of T-DM1 compared with capecitabine and lapatinib (one year: 85.2% vs. 78.4%; two years: 64.7% vs. 51.8%). (Figure 1)
  • Subgroup analyses of OS revealed that T-DM1 was the better treatment option in nearly every patient subgroup, except for those with nonvisceral disease (n = 322, HR = 1.05 [95% CI: 0.69–1.61]) and in patients who were ≥75 years old (n = 25, HR = 3.45 [95% CI: 0.94–12.65]). (Figure 2)
  • Patients in the T-DM1 arm had a statistically significant increase in OR rate compared with those in the capecitabine and lapatinib arm (43.6% vs. 30.8%, a difference of 12.7% [95% CI: 6.0–19.4%]; p = 0.0002). (Figure 3)
  • The DR was longer in patients treated with T-DM1 compared with capecitabine and lapatinib (12.6 months [95% CI: 8.4–20.8] vs. 6.5 months [95% CI: 5.5–7.2]). (Figure 3)
  • Overall, the number of all-grade adverse events (AEs) was similar between the two treatment arms.
    • However, the proportions of patients experiencing grade ≥3 AEs (57.0% vs. 40.8%) and AEs leading to treatment discontinuation (10.7% vs. 5.9%) were increased in the capecitabine and lapatinib arm. (Table 1)
  • There were a total of five deaths as a result of AEs while on treatment, four in the capecitabine and lapatinib arm and one in the TDM-1 arm, all of which were attributed to AEs that occurred within 30 days after the last dose of a study drug. (Table 1)
  • A greater percentage of patients experienced grade ≥3 nonhematologic AEs in the capecitabine and lapatinib arm compared with the T-DM1 arm, including diarrhea (20.7% vs. 1.6%) and hand-foot syndrome (16.4% vs. 0.0%). (Table 2)
  • However, a greater percentage of patients in the T-DM1 arm experienced grade ≥3 AEs involving increased levels of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%). (Table 2)
  • The safety data for grade ≥3 hematologic AEs revealed that a greater percentage of patients in the T-DM1 arm developed thrombocytopenia (12.9% vs. 0.2%) and anemia (2.7% vs. 1.6%), while more patients in the capecitabine and lapatinib arm experienced neutropenia (4.3% vs. 2.0%). (Table 2)
  • Overall, the frequency of cardiac dysfunction AEs was low in both arms and there were no meaningful differences between groups. (Table 3)

Key conclusions

  • T-DM1 offered a significant and clinically meaningful improvement in PFS and OS compared to capecitabine and lapatinib.
  • In addition, T-DM1 showed a significant improvement in OR rate and DR as well as a favourable safety profile as compared to lapatinib and capecitabine which supports T-DM1 as an active and well tolerated novel therapy for patients with HER2-positive advanced breast cancer.

Reference 1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783–91. 2. Verma S, Miles D, Gianni L, et al. Updated overall survival results from EMILIA, a phase III study of trastuzumab emtansine(T-DM1) versus capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer. ESMO Congress 2012 Abstracts:LBA12.

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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.