NE Oncology Issue – April 2013

Hegg R, et al. ESMO 2012:273P

Background

The HannaH study demonstrated noninferiority of the fixed-dose subcutaneous (sc) formulation of trastuzumab compared with the intravenous (iv) formulation, based on pharmacokinetics and efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.1 The sc formulation of trastuzumab uses recombinant human hyaluronidase (rHuPH20) as an excipient, a locally acting and transient permeation enhancer, to facilitate the absorption of 5 mL volumes of trastuzumab. At the ESMO 2012 Congress, Hegg and colleagues presented the results of immunogenicity testing for both the sc and iv formulations of trastuzumab, one of the secondary objectives of the HannaH study.2

Study design

  • For information on study design and treatment protocols, see Melichar et al. on p. 30.
  • Samples for immunogenicity assessment (antidrug antibody [ADA] and neutralizing antibody [nAb]) were collected at baseline, on day 1 of cycles 2, 5 (presurgery), 13, and 18 (postsurgery) and at three, six, 12, 18, and 24 months following the last trastuzumab dose.
  • A total of 295 patients in each treatment arm were considered evaluable for ADA response to trastuzumab.
    • Five patients in the iv arm and eight in the sc arm had no baseline samples available.
  • The evaluation of both trastuzumab and rHuPH20 immunogenicity used tiered strategies to detect, confirm, and characterize ADA responses. Each tiered strategy included the following elements:
    • A screening assay to detect antitrastuzumab or anti-rHuPH20 antibodies;
    • A confirmatory assay to assess the specificity of screen positive samples by competition with excess trastuzumab or rHuPH20;
    • A titration assay to determine antitrastuzumab or anti-rHuPH20 antibody titres for confirmed positive samples.
  • Serial dilutions of all confirmed positives were performed in order to estimate the magnitude of a positive response. The highest dilution that produced a signal above the screening assay cutpoint multiplied by the assay minimum required dilution (1:10) was deemed the end-point titre and was expressed as a dilution factor (reciprocal of the dilution).
  • Any potential effects of ADAs (antitrastuzumab or anti-rHuPH20) on the efficacy (pharmacokinetics and pathologic complete response [pCR]) and safety (administration-related reactions [ARRs]) of trastuzumab were explored using descriptive statistics.

Key findings

  • Patients (n = 24) in the trastuzumab iv arm and 31 patients in the trastuzumab sc arm tested positive for ADAs prior to and/or after drug exposure.
  • At baseline, some patients in each arm tested positive for antitrastuzumab antibodies even before drug exposure (iv: 17/290 patients [5.9%] vs. sc: 12/287 patients [4.2%]). (Figure 1)
  • Of those patients who tested ADA-positive at baseline:
    • Most patients in both arms were ADA-negative at all postbaseline time points and were therefore excluded from determination of the overall ADA rate to trastuzumab (iv: 14/17 patients vs. sc: 11/12 patients).
    • Antitrastuzumab nAbs were detected in one patient from both study arms.
  • Only a few patients from either arm were confirmed positive for antitrastuzumab antibodies at more than one postbaseline time point at the clinical cut-off (iv: n = 2; sc: n = 1).
  • The highest trastuzumab ADA titre assay value was 800, found in one patient at baseline, and the highest postbaseline value was 400, found in a different patient at cycle 2.
  • Using a conservative approach, the overall ADA rates were 3.4% (10/295 patients) in the trastuzumab iv arm and 6.8% (20/295 patients) in the trastuzumab sc arm. (Figure 1)
  • The overall ADA rate for rHuPH20 was 11.5% (34/295 patients) in the trastuzumab sc arm. (Figure 1)
    • At baseline, 22/290 patients (7.6%) presented with antibodies to rHuPH20.
    • None of the patients had a positive result for nAbs to rHuPH20 at baseline or postbaseline.
  • The highest rHuPH20 ADA titre assay value at baseline was 2,560, found in one patient, and the highest postbaseline value was 1,280, detected in that same patient, as well as one other patient. (Figure 2)
  • Only one patient was identified as being ADA-positive to both trastuzumab and rHuPH20.
    • Following a negative baseline assessment in both ADA assays, the patient developed antibodies to trastuzumab at cycle 2 and to rHuPH20 at cycle 18.
    • The patient’s adverse event profile did not suggest any clinical relevance of this finding.
  • Analysis of the trough serum concentrations (Ctrough) of trastuzumab at cycles 8 and 13 showed that trastuzumab pharmacokinetics within each arm were similar regardless of antitrastuzumab antibody status or treatment cycle. (Figure 3)
    • However, higher Ctrough values of trastuzumab were found in patients receiving the sc formulation compared with those receiving the iv formulation.
  • Trastuzumab Ctrough was similar in both anti-rHuPH20 antibody-positive and negative patients. (Figure 4)
  • pCR rates for patients classified by antitrastuzumab (iv and sc) or anti-rHuPH20 (sc only) antibody status in each arm were similar regardless of ADA status for either type of ADA. (Figure 5)
  • The incidence of patients in each arm experiencing any ARRs during the study was not statistically different irrespective of their ADA status for either type of ADA. (Table 1)
  • The most commonly reported ARRs regardless of treatment arm or ADA status were skin and sc tissue disorders.

Key conclusions

  • Immunogenicity of trastuzumab sc, as determined by antitrastuzumab and anti-rHuPH20 antibody monitoring throughout the HannaH study, was found to be low overall.
  • Immunogenicity of trastuzumab and rHuPH20 had no clinical relevance as it did not affect efficacy (pCR rates), safety (ARRs), or trastuzumab pharmacokinetics (Ctrough).

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. Hegg R, Pienkowski T, Chen S-T, et al. Immunogenicity of trastuzumab intravenous and subcutaneous formulations in the phase III HannaH study. ESMO Congress Abstracts 2012:273P.

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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.