NE Oncology Issue – April 2013

Diéras V, et al. SABCS 2012:P5-18-06


The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) combines the antitumour activities of trastuzumab with intracellular delivery of the cytotoxic agent DM1 and represents a new approach to therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Recently, the first phase III data reported significant improvements in PFS (9.6 versus 6.4 months; HR = 0.650, p <0.001) and lower incidence of grade ≥3 adverse events (AEs) (57% versus 41%) versus capecitabine plus lapatinib.1 At the 2012 SABCS, Diéras and colleagues presented a pooled analysis of safety from all T-DM1 trials summarizing the AEs encountered in patients treated with T-DM1.2

Study design

  • Data were included from patients with unresectable locally advanced or metastatic breast cancer (N = 882) enrolled in six clinical trials or in an extenstion study treated with single-agent T-DM1 (3.6 mg/kg every three weeks): TDM4370g, TDM4450g, TDM4374g, TDM4258g, TDM4688g, TDM3569g, and TDM4529g. (Table 1)
  • All studies assessed AEs, basic laboratory data, vital signs, physical examination findings, and left ventricular ejection fraction (LVEF) as per the schedules mandated by the respective protocols; laboratory assessments typically occurred weekly during the first several treatment cycles.
  • AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
  • AEs were reported up to 30 days after the last dose of study medication, until the early termination visit, or at the initiation of another anticancer therapy, whichever occurred first.
    • After this period, investigators reported only deaths from any cause and serious AEs (SAEs) that were considered related to prior study treatment.


Key findings

  • The baseline characteristics among patients in all T-DM1 studies included:
    • Median age: 53 years (range, 25–85 years);
    • Percentage with ≥three metastatic sites: 52.7%;
    • Percentage receiving prior treatment for MBC: 81.7%;
    • Median number of prior nonhormonal agents: 5 (range, 0–19).
  • The most commonly reported AEs of any grade occurring in ≥20% of patients were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%). (Table 2)
  • Grade 3/4 AEs occurring in ≥2% of patients were thrombocytopenia (10.2%), increased aspartate aminotransferase (AST) (4.1%), increased alanine aminotransferase (ALT) (2.8%), fatigue (3.2%), hypokalemia (2.9%), and anemia (2.5%). (Table 2)
  • A total of 55 patients (6.2%) exposed to T-DM1 discontinued treatment because of an AE.
    • The most commonly reported events leading to discontinuation involved laboratory abnormalities, primarily thrombocytopenia (1.4%), and increased hepatic transaminases (0.8% for increased AST and 0.5% for increased ALT).
    • These laboratory abnormalities were also the most frequently reported reasons for dose reductions.
  • During treatment or within 30 days of their last T-DM1 dose, nine patients experienced AEs that led to death (reported by investigators as hepatic failure, hepatic function abnormal, bacterial sepsis, pneumonia, metabolic encephalopathy, respiratory failure [two cases], interstitial lung disease, and sudden death).
    • Of these deaths, four were deemed by the investigator to be related to treatment with T-DM1: hepatic failure, hepatic function abnormal, bacterial sepsis, and metabolic encephalopathy.


  • Increases in mean AST and ALT values were generally transient, usually appeared by the first measurement after dosing (day 8), and generally returned to baseline or the normal range by the next scheduled dose.
    • Most cases of grade 3 ALT increases returned to grade 1/2 within one or two cycles.
    • The proportion of patients with grade ≥3 increased transaminases did not increase over time.
    • Most patients continued T-DM1 treatment with appropriate dose modifications.

Thrombocytopenia and hemorrhage

  • Thrombocytopenia was the primary dose-limiting toxicity associated with T-DM1 in the dose-ranging trial.
    • In this safety analysis, 28.7% of T-DM1 treated patients experienced thrombocytopenia and the majority were grade 1/2 (64.4%).
  • Grade 3/4 thrombocytopenia generally occurred within the first 2 treatment cycles.
  • Thrombocytopenia was not reversible in all patients; however, with appropriate dose modifications, platelet counts did recover sufficiently to allow treatment to continue in nearly all patients.
  • To better explore the relationship between thrombocytopenia and hemorrhage, the incidences of thrombocytopenia and hemorrhage were cross-tabulated. (Table 3)
    • Of the 122 patients with grade 3/4 thrombocytopenia:
      • Grade 1 bleeding was experienced by 51 (41.8%) patients;
      • Grade 2 bleeding was experienced by four (3.3%) patients;
      • Grade 3/4 bleeding was experienced by six (4.9%) patients.
      • Grade 3/4 bleeding events and grade 3/4 thrombocytopenia did not occur concurrently in any patients.

Cardiac safety

  • Cardiac dysfunction (i.e., cardiac failure [SMQ (Standardized MedDRA Queries) narrow]) was infrequent (1.5%), and the majority of patients (11 of 13) experienced grade 1/2 events. The remaining two events were grade 3 decreased ejection fraction.
  • Four (0.5%) patients had a post-baseline LVEF <40% and 16 (1.8%) patients had an LVEF decline of ≥15 percentage points from baseline to below 50%.
  • A total of three (0.3%) patients discontinued T-DM1 because of a cardiac disorder (one atrial fibrillation, one left ventricular dysfunction, and one decreased ejection fraction).

Key conclusions

  • The safety profile of T-DM1 was consistent across the studies and the different patient populations with HER2-positive MBC.
  • The safety profile of T-DM1 observed in this analysis is consistent with the theoretical concept underlying the design of ADCs — that targeting the delivery of chemotherapy to tumour cells and restricting chemotherapy release to the intracellular compartment reduces systemic toxicity.

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. Diéras V, Harbeck N, Budd GT, et al. Trastuzumab emtansine in HER2-positive metastatic breast cancer: pooled safety analysis from seven studies. SABCS Annual Meeting Abstracts 2012:P5-18-06.

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Canadian Perspectives


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.


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


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.


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.


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.