NE Oncology Issue – April 2013

Melichar B, et al. ESMO 2012:254PD


The current standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer includes intravenous (iv) therapy with trastuzumab over a 30-to-90 minute infusion period.1 A subcutaneous (sc) formulation of trastuzumab was recently developed that can be administered to patients in approximately five minutes, which would considerably improve the cost-effectiveness and convenience of this treatment.1 The HannaH study is a clinical trial in the neoadjuvant and adjuvant setting for patients with HER2-positive early breast cancer (EBC) designed to assess whether the fixed-dose sc formulation of trastuzumab is comparable with its registered iv formulation.1 Melichar and colleagues presented patient subgroup analyses of the coprimary end points for this study at the ESMO 2012 Congress.2

Study design

  • The HannaH study (NCT00950300) is a phase III, randomized, open-label, multicentre, noninferiority clinical trial of trastuzumab sc vs. trastuzumab iv comparing the pharmacokinetics, efficacy, and safety of both formulations in patients with HER2-positive EBC (clinical stages I to III).
  • Patients were randomized (1:1) to receive eight cycles of neoadjuvant chemotherapy once every three weeks (q3w) as follows:
    • Four cycles of docetaxel (75 mg/m2), followed by:
    • Four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (500/75/500 mg/m2);
    • Administered concurrently with:
    • Trastuzumab by either iv (8 mg/kg loading dose followed by 6 mg/kg maintenance dose, q3w) or sc (600 mg fixed dose, q3w).
  • After surgery, patients continued to receive trastuzumab, as per the initial randomization, to complete one year of treatment.
  • The coprimary end points of the HannaH study were:
    • Pathologic complete response (pCR);
    • Observed trough serum concentration (Ctrough) of trastuzumab at predose cycle 8.
  • The aims of the patient subgroup analyses were to explore:
    • Whether pCR rates for trastuzumab sc vs. trastuzumab iv were comparable across various patient subgroups;
    • Factors that may influence pCR in patients receiving neoadjuvant trastuzumab-based therapy for HER2-positive breast cancer;
    • A potential relationship between pCR rate, body weight, and pharmacokinetics (Ctrough) of trastuzumab.

Key findings

  • A total of 596 patients (trastuzumab iv arm [n = 299] and trastuzumab sc arm [n = 297]) were enrolled into the study between October 2009 and December 2010.
  • The median follow-up period was approximately 12 months at the time of clinical cut-off (July 12, 2011), at which point all patients had undergone surgery and 116 patients in each arm had completed adjuvant treatment.
  • Previously published results for this study demonstrated the noninferiority of trastuzumab sc vs. trastuzumab iv.
    • The pCR rates were 45.4% in patients receiving trastuzumab sc and 40.7% in those receiving trastuzumab iv.1
  • Analyses of the differences in pCR rates between treatment arms for each subgroup had confidence intervals (CIs) that contained zero, indicating a lack of statistical significance.
    • However, point estimates for the differences in pCR rates were trending in favour of the trastuzumab sc arm in the majority of these exploratory subgroup analyses. (Figure 1)
  • In two small subgroups, point estimates for the differences in pCR rates between treatment arms were trending in favour of the trastuzumab iv arm:
    • Patients aged ≥65 years (n = 47): –20.6 (95% CI: –51.8–10.66);
    • Patients with inflammatory breast cancer (IBC) (n = 34): –19.3 (95% CI: –56.4–17.83). (Figure 1)
  • In the trastuzumab iv arm of the study, pCR rates for patients ≥65 years old (65.0%) and patients with IBC (66.7%) were much higher than the pCR rate observed for the overall trastuzumab iv population (40.7%).
    • In contrast, pCR rates for the same patient subgroups in the trastuzumab sc arm, ≥65 years old (44.4%) and IBC (47.4%), were consistent with the pCR rate observed in the overall trastuzumab sc population (45.4%).
  • Also, in the same subgroups, a greater proportion of patients with estrogen receptor (ER)-negative tumours were detected in the trastuzumab iv arm compared with the trastuzumab sc arm:
    • Patients ≥65 years old: 75% vs. 56%;
    • Patients with IBC: 67% vs. 42%.
  • The adjusted odds ratio (OR) for pCR in the trastuzumab sc arm vs. the iv arm was 1.30 (95% CI: 0.90–1.88) and was, therefore, consistent with the unadjusted OR of 1.21 (95% CI: 0.86–1.71). (Table 1)
  • Patients with ER-negative tumours (including one tumour with unknown ER status) had a significantly higher probability of attaining a pCR compared with those who had ER-positive tumours (OR = 2.68 [95% CI: 1.85–3.87]; p <0.0001). (Table 1)
  • The estimated ORs for pCR were similar for different body weight quartiles and Ctrough values, showing that neither body weight nor serum Ctrough of trastuzumab was correlated with pCR rate in either treatment arm. (Figure 2)
  • Similar pCR rates were observed in both treatment arms for patients in all body weight quartile groups, except for the lowest quartile group (<58 kg) in which a slight difference in pCR rates was identified between the sc and iv treatment arms (54% and 37%, respectively). (Table 2)
  • Additional analyses in patients with a higher body weight revealed similar pCR rates for both treatment arms:
    • Patients weighing ≥90 kg (n = 55): 40% in the sc arm and 44% in the iv arm;
    • Patients weighing ≥100 kg (n = 18): 50% in both the sc and the iv treatment arms.

Key conclusions

  • Efficacy of the sc formulation of trastuzumab, measured by means of pCR, is comparable with the iv formulation and consistent across subgroups of patients with HER2-positive breast cancer.
  • ER-negative tumour status at baseline was the only independent factor associated with patients achieving pCR, which is consistent with the published literature.
  • The 600 mg fixed dose of trastuzumab sc formulation is efficacious, irrespective of patient body weight. Patient body weight and serum Ctrough of trastuzumab do not appear to influence the pCR rate achieved with the sc formulation of trastuzumab.
  • The sc formulation is a promising alternative to the iv formulation of trastuzumab.

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. Melichar B, Stroyakovskiy D, Ahn JS, et al. Pathological complete response to trastuzumab subcutaneous fixed-dose formulation in the HannaH study: subgroup analysis of patient demographics and tumour characteristics and influence of body weight and serum trough concentration of trastuzumab. ESMO Congress Abstracts 2012:254PD.

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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.