NE Oncology Issue – April 2013

Pivot X, et al. ESMO 2012:LBA5; SABCS 2012:S5-3

Background

Since 2005, treatment with trastuzumab for one year has provided survival benefit to patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). However, the optimal duration of trastuzumab in the adjuvant setting has been debated, as no large randomized trials have compared the standard duration of one year with a longer or shorter treatment. There was recently some discussion about the results from the FinHer trial,1 which compared nine weeks of adjuvant trastuzumab plus chemotherapy versus chemotherapy alone. The authors found a trend in favour of trastuzumab, but results were not statistically significant and the study did not compare the nine week regimen to today’s standard of care of one year of adjuvant trastuzumab. The French National Cancer Institute initiated a randomized noninferiority trial to compare a shorter trastuzumab exposure of six months versus the standard of 12 months. The results of this trial, named PHARE (Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure) were presented by Pivot and colleagues at the ESMO 2012 Congress, with additional subgroup analyses shown at the SABCS 2012.2,3

Study design

  • The PHARE trial (NCT00381901) is a randomized, controlled, multicentre study that was approved by an independent ethics committee with regularly planned independent data monitoring committee (IDMC) meetings.
  • Patients with HER2-positive EBC who had received at least four cycles of (neo)adjuvant chemotherapy were eligible.
  • Randomization (1:1) of patients to the control arm (12 months of trastuzumab) or the experimental arm (six months of trastuzumab) used a minimization algorithm that stratified patients based on concomitant or sequential trastuzumab administration with chemotherapy, estrogen receptor (ER) status, and treatment centre.
  • The primary objective was to compare disease-free survival (DFS).
  • An absolute loss of 2% in DFS in the experimental arm was defined as the noninferiority margin (1.15 in relative terms), which required an accrual of 3,400 patients to reach 1,040 DFS events for 80% power at an alpha of 5%.

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Key findings

  • Between May 2006 and July 2010, 3,380 patients (n = 1,690 per arm) were randomized to six or 12 months of trastuzumab following the IDMC recommendation for accrual suspension and extended follow-up.
  • For these analyses, the database was locked on July 31, 2012, and the median follow-up was 42.5 months since randomization.
  • Demographics, prior treatments, and disease characteristics for patients at baseline were well balanced between the two arms.
  • DFS rates with six months of trastuzumab were slightly lower than 12 months of trastuzumab at 12 months (95.5% vs. 97.0%), 24 months (91.2% vs. 93.8%), 36 months (87.8% vs. 90.7%), and 48 months (84.9% vs. 87.8%) following randomization. (Figure 1)
  • The DFS hazard ratio (HR) in the six months vs. 12 months of trastuzumab cohorts showed that the 95% confidence interval (CI) contained the prespecified noninferiority margin of 1.15, with a trend towards worse DFS in the shorter duration arm (HR = 1.28 [95% CI: 1.05-1.56], p = 0.29). (Figure 1)
  • A greater proportion of patients treated with trastuzumab for six months experienced a DFS event of any kind compared with those who were treated for 12 months (13.0% vs. 10.4%), with distant recurrence (8.3% vs. 6.4%) being the greatest difference between the two arms. (Table 1)
  • Exploratory analysis of the HRs for DFS by patient subgroup showed that the 95% CIs in every category crossed the noninferiority boundary of 1.15, indicating that noninferiority could not be demonstrated and that there was a trend favouring 12 months of trastuzumab. (Figure 2)
  • Subgroup analyses based on the combination of two stratification factors, ER status in the tumour (positive or negative) and treatment modality (trastuzumab and chemotherapy given concomitantly or sequentially), suggested that of the four group combinations, the DFS for patients with ER negative tumours on the sequential modality had an effect on the overall results with a trend favouring 12 months of trastuzumab (HR = 1.57 [95% CI: 1.08–2.28]). (Figure 2)
    • However, the 95% CIs for each subgroup were large and did cross the noninferiority margin.

Key conclusions

  • PHARE failed to show that six months of trastuzumab is noninferior to 12 months of trastuzumab in the adjuvant setting for patients with HER2-positive EBC.
  • Although the subgroup analyses were exploratory and conducted in order to generate hypotheses for future clinical trials, they revealed the following: • None of the subgroups could demonstrate noninferiority of 6 months compared with 12 months of adjuvant trastuzumab and all subgroups showed a trend favouring the current standard of care of one year of trastuzumab.
    • The sequential modality for ER-negative tumours may have had an impact on the overall results.
  • Longer follow-up of PHARE and the results of other trials testing the duration of adjuvant trastuzumab, such as PERSEPHONE, SHORTER, and SOLD (Synergism or Long Duration), are expected to provide additional data in the future.
  • As a result, one year of trastuzumab remains the standard of care in the adjuvant treatment of EBC for all patient subgroups.

References: 1. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol 2009;27:5685–92. 2. Pivot X, Romieu G, Bonnefoi H, et al. PHARE trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. Ann Oncol 2012;23:ixe1–ixe30 (LBA5). 3. Pivot X, Romieu G, Bonnefoi H, et al. PHARE Trial results of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. SABCS Annual Meeting Abstracts 2012:S5-3.

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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.