NE Oncology Issue – April 2013

Jackisch C, et al. ESMO 2012:271P

Background

The primary analysis of the data from the HannaH study demonstrated that, in the neoadjuvant/ adjuvant setting, the pharmacokinetics and efficacy of a new fixed-dose subcutaneous (sc) formulation of trastuzumab were equivalent to the registered intravenous (iv) formulation for patients with HER2- positive early breast cancer.1 At the time of the primary analysis, the safety profiles of both formulations were also comparable. In this presentation given at the ESMO 2012 Congress, Jackisch and colleagues further characterized and compared the safety profiles of the sc and iv formulations of trastuzumab.2

Study design

  • For information on study design and treatment protocols, see Melichar et al. on p. 30.
  • Safety, including cardiac monitoring, was assessed by physical examination, vital signs, and laboratory parameters every three months during the treatment period until 24 months after the last dose of trastuzumab.
  • Assessments are continuing during the follow-up period, with cardiac monitoring continuing for five years after the end of trastuzumab treatment.
  • Adverse event (AE) assessment continues by three methods:
    • AEs: National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0;
      • Grade 3–5AEs are classed as “severe” for the purpose of these analyses.
    • Serious AEs (SAEs): adhering to local guidelines and the full requirements of International Conference on Harmonization E2A.
    • Congestive heart failure: New York Heart Association classification.
  • Safety analyses in this presentation were conducted at a median follow-up of 20 months (vs. 12 months in the primary analysis) on the safety population, defined as all patients who received at least one dose of study treatment ([iv, n = 298] and [sc, n = 297]).

Key findings

  • An overview of the two safety profiles showed that the incidence of patients experiencing AEs of any kind was relatively similar for both treatment arms. (Table 1)
  • The incidence of patients experiencing ≥one AE of any grade remained similar in the iv vs. sc arms (94.6% vs. 97.6%). (Table 1)
  • The most common AEs of any grade were (iv vs. sc): Alopecia (62.8% vs. 63.0%), nausea (49.3% vs. 48.8%), neutropenia (47.0% vs. 44.1%), diarrhea (36.9% vs. 34.0%), fatigue (26.8% vs. 23.2%), and asthenia (25.2% vs. 24.6%).
  • The incidence of patients with ≥one severe AE was also similar in the iv vs. sc arms (52.3% vs. 53.5%). (Table 1)
  • The most common severe AEs (grades 3–5) were (iv vs. sc):
    • Hematological AEs (37.2% vs. 35.4%), gastrointestinal AEs (6.4% vs. 5.7%), and infections (5.0% vs. 7.1%).
  • More patients in the trastuzumab sc arm vs. the trastuzumab iv arm experienced ≥one SAE (21.9% vs. 13.4%). (Table 1)
    • Consistent with the primary analysis, increased reporting of SAEs in the “infections” disease category for patients receiving the sc vs. iv formulations (8.1% vs. 4.4%) remains the most influential driver for the imbalance.
  • Two patients (0.7%) died in the iv arm compared with four patients (1.3%) in the sc arm. (Table 1) AEs leading to death were pneumonia and myeloid leukemia in the iv arm and sudden death, septic shock, myocardial infarction, and endometrial cancer in the sc arm. In all cases, the patients could be considered to have been at risk because of conditions present when treatment began.
  • The distribution of all incidences of AEs and SAEs by severity in the iv and sc arms was balanced, including grade 3–5 AEs and SAEs in the two arms. (Table 2)
    • Grade 3–5 AEs (iv vs. sc): 8.6% (369/4,304) vs. 7.8% (343/4,370).
    • Grade 3–5 SAEs (iv vs. sc): 77.4% (41/53) vs. 77.7% (73/94).
  • The severity of AEs was similar in both arms; however, AEs of grade 3/4 were more frequently classified as SAEs in the sc arm than in the iv arm. (Table 2)
  • The incidence of cardiac AEs was also similar between the two arms (13.1% [iv] vs. 12.8% [sc]) and consistent with the primary analysis.
  • Patients assessed in the sc arm (9/292 [3.1%]) and in the iv arm (11/289 [3.8%]) had a significant left ventricular ejection fraction decrease of ≥10 percentage points from baseline to <50% in the current analysis.
  • Multiple logistic regression analyses did not show a correlation between severe AEs or SAEs and body weight and/or drug exposure for trastuzumab sc.
  • Chi-square tests for equality of rates between quartiles of patients in the trastuzumab sc arm, classified by body weight and drug exposure, indicated that there were no significant differences in severe AEs or SAEs with respect to either factor (both p-values >0.5).
  • Some patients in each arm were withdrawn from treatment due to AEs (iv, n = 8 [2.7%] vs. sc, n = 17 [5.7%]). (Table 3)
    • After withdrawal from treatment, patients saw most of their AEs resolve.
  • More patients in the sc arm than the iv arm were withdrawn from treatment due to cardiac disorders (sc, n = 9 [3.0%] vs. iv, n = 5 [1.7%]). (Table 3)
  • Two patients in the iv arm compared with none in the sc arm were withdrawn from treatment due to AEs reported in the “infections” category (one for hepatitis B and one for pneumonia). (Table 3)
  • The apparent imbalance in respiratory, thoracic, and mediastinal disorders in the sc arm vs. the iv arm (4 vs. 0) was due to pre-existing conditions in three patients and radiation pneumonitis in the fourth patient. (Table 3)

Key conclusions

  • At a median follow-up of 20 months, the safety profiles of the iv and sc formulations of trastuzumab were comparable and consistent with the known safety profile of trastuzumab iv. All patients have now entered the treatment-free follow-up phase.
  • Overall, all AEs were balanced across treatment arms. While rates of severe AEs were balanced, rates of serious AE reporting were not. If this reflected a true imbalance due to clinically relevant AEs, one would expect this to be reproduced by the distribution of severe (grade 3–5) AEs, which it was not, suggesting that patient management differed across the arms of this open-label trial, with a more conservative approach taken in the sc arm.
  • There are no safety concerns (in particular in patients <51 kg) with the use of a fixed 600 mg dose of trastuzumab sc compared with standard iv treatment.

References: 1. Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 2012;13:869–78. 2. Jackisch C, Dank M, Frasci G, et al. Additional safety results of HannaH: a phase III randomised, open-label, international study of the subcutaneous formulation of trastuzumab in HER2-positive early breast cancer patients. ESMO Congress Abstracts 2012:271P.

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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.