NE Oncology Issue – April 2013

Goldhirsch A, et al. ESMO 2012:LBA6; SABCS 2012:S5-2

Background

In 2005, the HERA (HERceptin® Adjuvant) trial and other large randomized trials demonstrated a statistically significant disease-free survival (DFS) benefit for one year of trastuzumab compared with observation alone following adjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)- positive early breast cancer (EBC).1,2 The protocol for the HERA trial was subsequently revised in order to shift the focus to the secondary objective of assessing whether trastuzumab administered for a period of two years was superior to one year of treatment with the drug. At the 2012 ESMO Congress and SABCS, new data by Goldhirsch and colleagues was presented comparing the efficacy and safety of these two periods of trastuzumab after a median eight years of follow-up, as well as additional analyses of one-year trastuzumab versus clinical observation.2,3

Study design

  • The patients (N = 5,102) accrued from 2001 to 2005 for the HERA trial (NCT00045032) were diagnosed with locally determined HER2-positive, invasive EBC.
  • All patients underwent treatment with surgery and (neo)adjuvant chemotherapy with or without radiotherapy and were required to have central confirmation of HER2-positive breast cancer (immunohistochemistry 3+ or fluorescence in situ hybridization +) and a left ventricular ejection fraction ≥55% before randomization.
  • Having met these criteria, patients were randomly assigned to one of three groups:
    • Observation (n = 1,698);
    • One year of trastuzumab (n = 1,703, iv infusion of 8 mg/kg initial loading dose; 6 mg/kg thereafter, once every three weeks [q3w]);
    • Two years of trastuzumab (n = 1,701, iv infusion of 8 mg/kg initial loading dose; 6 mg/kg thereafter, q3w).
  • Patients in the observation arm were given the option of switching to trastuzumab after trial results were presented at ASCO in 2005. This enabled 885 (52.1%) of 1,698 patients in the observation group to selectively cross over.
  • The following analysis included patients who remained diseasefree for at least 366 days after randomization to the trastuzumab arms (one year: n = 1,552 and two years: n = 1,553).

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Key findings

  • Baseline characteristics for patients in both trastuzumab arms were well balanced.
  • Despite the complication of selective crossover from observation to trastuzumab after disclosure of first results in 2005, intent-to-treat (ITT) analyses at long-term followup indicated that one year of trastuzumab compared with observation significantly improved DFS in all patients, regardless of their hormone receptor status:
    • DFS (one year trastuzumab vs. observation): (Figure 1)
      • All patients (HR = 0.76; 471 vs. 570 events, p <0.0001);
      • Hormone receptor positive (HR = 0.81, 218 vs. 253 events, p = 0.0258);
      • Hormone receptor negative (HR = 0.72, 253 vs. 317 events, p <0.0001).
  • In addition, ITT analyses of patients in the one-year trastuzumab arm demonstrated a statistically significant OS benefit. In a subgroup analysis, trastuzumab provided a significant OS benefit in the hormone receptor negative group and a trend towards OS benefit for the hormone receptor positive group.
    • OS (one year trastuzumab vs. observation): (Figure 2)
      • All patients (HR = 0.76; 278 vs. 350 events, p = 0.0005);
      • Hormone receptor positive (HR = 0.84, 126 vs. 146 events, p = 0.1425);
      • Hormone receptor negative (HR = 0.70, 152 vs. 204 events, p = 0.0007).
  • At a median follow-up of eight years, a total of 734 DFS events were reported for both trastuzumab groups (367 events in each arm).
    • Two years vs. one year of trastuzumab were not significantly different in terms of DFS (hazard ratio [HR] = 0.99 [95% CI: 0.85–1.14], p = 0.86). (Figure 3)
    • Also, the DFS rates for patients receiving two years vs. one year of trastuzumab were similar at two years (89.1% vs. 86.7%), four years (81.6% vs. 81.0%), and eight years (75.8% vs. 76.0%) following randomization. (Figure 3)
  • At those same time points, the DFS rates for patients subdivided by hormone receptor status were also similar for both treatment arms, except for a slight advantage for hormone receptor negative patients receiving two years vs. one year of trastuzumab (87.8% vs. 83.8%); this was observed at three years from randomization.
  • Overall, no significant benefit in DFS was detected for two years vs. one year of trastuzumab in patients with tumours that were hormone receptor positive (HR = 1.05 [95% CI: 0.85–1.29], p = 0.67) or hormone receptor negative (HR = 0.93 [95% CI: 0.76–1.14], p = 0.51).
  • An overview of DFS events, such as regions of disease recurrence, contralateral breast cancer, second (primary) malignancies, and death, showed that each type was experienced by comparable proportions of patients in the trastuzumab arms. (Table 1)
  • Overall survival (OS) rates were similar for patients receiving two years vs. one year of trastuzumab following two years (97.4% vs. 96.5%), four years (92.6% vs. 91.4%), and eight years (86.4% vs. 87.6%) after randomization. (Figure 4)
  • The longer duration of trastuzumab (two years vs. one year) was not significantly more beneficial for OS (HR = 1.05 [95% CI: 0.86–1.28], p = 0.63). (Figure 4)
  • In the safety analysis population, adverse events (AEs) occurred in slightly more patients in the two-year trastuzumab arm than the one-year arm, both of which had a greater frequency of AEs compared with observation alone (two years vs. one year vs. observation): (Table 2)
    • ≥One grade 3/4 AE: 20.4% vs. 16.3% vs. 8.2%;
    • Fatal AE: 1.2% vs. 1.1% vs. 0.4%;
    • Primary cardiac AE: 1.0% vs. 0.8% vs. 0.1%;
    • Secondary cardiac AE: 7.2% vs. 4.1% vs. 0.9%.
  • While the cumulative incidence of primary cardiac end points was similar in the trastuzumab arms, primary or secondary cardiac end points were met more frequently in patients receiving two years vs. one year of trastuzumab (8.2% vs. 4.9%). (Table 2)

Key conclusions

  • HERA results at 8 years MFU show sustained and statistically significant DFS and OS benefit for one year trastuzumab versus observation in ITT analyses despite selective crossover.
  • Benefit for one year trastuzumab, compared to observation, was shown across hormone receptor positive and negative cohorts.
  • Patients with HER2-positive EBC derived no added long-term benefit in DFS or OS from two years compared with just one year of trastuzumab when administered as sequential treatment following chemotherapy.
  • While the majority of cardiac end points occurred with trastuzumab administration, they were generally infrequent and reversible.
  • One year of trastuzumab remains the standard of care as part of an adjuvant therapy for patients with HER2-positive early breast cancer.

References: 1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–72. 2. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. ESMO Congress Abstracts 2012:LBA6. 3. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. SABCS Annual Meeting Abstracts 2012:S5-2.

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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.