NE Oncology Issue – May 2014

Swain SM, et al. SABCS 2013:P4-12-10


In the phase III trial CLEOPATRA, patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) were treated with pertuzumab, trastuzumab, and docetaxel, resulting in significant improvements in progression-free survival (PFS) and overall survival (OS) compared with placebo plus trastuzumab plus docetaxel. Adverse events (AEs) were generally balanced between groups. However, the incidence of febrile neutropenia was almost doubled in patients treated in the pertuzumab arm compared with the placebo arm. An analysis of febrile neutropenia by geographic region showed that, among patients from Asia, 12% in the placebo arm and 26% in the pertuzumab arm experienced febrile neutropenia, whereas in all other geographic regions the incidence was no more than 10% in either treatment arm. The objective of this study was to investigate the safety profile of the study combinations and the exposure to docetaxel in patients from Asia compared with patients from all other geographic regions.1

Study design

  • CLEOPATRA was a double-blind, placebo-controlled, international phase III study.
  • Patient eligibility criteria included the following:
    • HER2+ locally recurrent, unresectable, or MBC;
    • No prior chemotherapy or biologic therapy for metastatic disease;
    • One hormonal treatment regimen for MBC before randomization allowed;
    • Eastern Cooperative Oncology Group performance status 0 or 1;
    • Left ventricular ejection fraction ≥50% at baseline.
  • Patients were randomized to receive either:
    • Placebo arm: placebo, trastuzumab, and docetaxel; or
    • Pertuzumab arm: pertuzumab, trastuzumab, and docetaxel.
  • Study drugs were administered intravenously on a 3-weekly schedule.
    • Pertuzumab/placebo: 840 mg initial dose, 420 mg subsequent doses.
    • Trastuzumab: 8 mg/kg initial dose, 6 mg/kg subsequent doses.
      • Treatment with pertuzumab/placebo and trastuzumab was given until disease progression or unacceptable toxicity.
    • Docetaxel: initiated at 75 mg/m2.
      • Dose escalation to 100 mg/m2 was allowed if tolerated.
      • Two dose reductions by 25% to 75 mg/m2 and 55 mg/m2 were allowed to manage toxicities.
      • Use of granulocyte-colony-stimulating factors (G-CSFs) was allowed for the treatment of febrile neutropenia and as prophylaxis as per the American Society of Clinical Oncology guidelines. Docetaxel dose reductions were the preferred measure for prevention of febrile neutropenia in subsequent cycles.
      • At least six cycles of docetaxel were recommended; fewer cycles were allowed for disease progression or unacceptable toxicity, more cycles were allowed at the discretion of the investigator.
  • The primary endpoint was PFS by independent assessment.
  • Secondary endpoints included OS, PFS by investigator assessment, objective response rate, and safety.
  • AEs were monitored continuously and graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0.
  • Tumour assessments were performed every nine weeks by the investigator and an independent review facility.
  • Data cutoff was in May 2011 except for the OS analysis with a data cutoff in May 2012.


Key findings

  • Patients (N = 808) were enrolled from 25 countries in Asia, Europe, North America, and South America (Europe, North America, and South America are referred to as “other regions”). Participating countries from Asia were China (including Hong Kong), Japan, Korea, the Philippines, Singapore, and Thailand.
  • A total of 128 and 125 patients in the placebo and pertuzumab arms, respectively, were from Asia.
  • The median time on study treatment was 11.8 months for patients in the placebo arm and 18.1 months for patients in the pertuzumab arm.
  • The proportion of patients who underwent a docetaxel dose escalation to 100 mg/m2 was 2.4% of those from Asia vs. 18.7% of those from other regions. (Table 1)
  • Docetaxel dose reductions below 75 mg/m2 were carried out in 47.0% of patients from Asia compared with 13.4% of patients from other regions. • AEs (all grades) that were reported with an incidence of at least 25% in patients from Asia and the incidences of febrile neutropenia and left ventricular systolic dysfunction are presented in Table 2.
    • The incidence of febrile neutropenia was 11.7% in the placebo arm vs. 25.6% in the pertuzumab arm in patients from Asia.
    • Similarly, the incidence of mucosal inflammation was doubled in the pertuzumab arm (36.8%) compared with the placebo arm (18.0%) in patients from Asia.
  • To analyze whether the incidence of febrile neutropenia was associated with patient weight and height, the rates of febrile neutropenia were compared by weight, body surface area, and body mass index quartiles (data not shown).
    • There was no trend for patients in the lower quartiles, irrespective of geographic region and treatment received, to be more likely to experience febrile neutropenia than patients in the upper quartiles.
  • Exploratory analyses of PFS and OS by region supported the results for the whole intention-to-treat population with hazard ratios being similar. (Figure 1)

Key conclusions

  • The higher overall incidence of AEs in patients from Asia did not result in a higher study treatment discontinuation rate
    due to AEs (Asia: 4.0%; other regions: 6.5%).

    • This suggests that dosing guidelines and support measures were successfully applied.
  • The median number of all study treatment and docetaxel cycles was not reduced in patients from Asia; at least 95% of
    patients received a minimum of six cycles of docetaxel.
  • Docetaxel dose reductions below 75 mg/m2 occurred in 47% of patients from Asia compared with 13% of patients from
    other regions. However, this did not adversely affect efficacy in patients from Asia, with PFS and OS being comparable
    with that of patients from other regions.

    • A reduction in the docetaxel starting dose should be considered in patients from Asia.
  • Overall, the benefit-risk profile of pertuzumab plus trastuzumab plus docetaxel supports this regimen as the preferred
    therapy for patients with HER2+ first-line MBC from Asia and all other geographic regions.

Reference: 1. Swain SM, Im Y-H, Im S-A, et al. Safety of pertuzumab with trastuzumab and docetaxel in patients from Asia with HER2-positive metastatic breast cancer: results from the phase III trial CLEOPATRA. SABCS Abstracts 2013:P4-12-10.

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Canadian Perspectives


Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.



Douglas A. Stewart, BMSc, MD, FRCPC
Dr. Douglas A. Stewart is currently a professor in the Departments of Oncology and Medicine, and Chief of the Division of Hematology and Hematological Malignancies at the University of Calgary. Since July 1994, he has been practising medical oncology at the Tom Baker Cancer Centre in Calgary, where he is a member of the Breast Cancer and Hematology Tumour Groups, Leader of the Hematology/Blood and Marrow Transplant Program, and Provincial Leader of the Hematology Tumour Team for the Alberta Health Services Cancer Care Program. His research interests focus on clinical trials involving hematological malignancies and hematopoietic stem cell transplantation. Dr. Stewart has authored over 80 peer-reviewed manuscripts and over 120 abstracts.

Investigator Commentary


Richard R. Furman, MD

Dr. Furman is a member of the Lymphoma/Myeloma Service in the Division of Hematology/ Oncology at the New York Weill Cornell Medical Center. He is head of the chronic lymphocytic leukemia (CLL) and Waldenstrom’s macroglobulinemia (WM) program at Weill Medical College, and focuses on identifying new and promising therapies for patients with CLL and WM. Along with collaborators at Columbia Presbyterian, Johns Hopkins, Roswell Park Cancer Institute, and Ohio State University, Dr. Furman has initiated the Waldenstrom’s Research Consortium in order to enhance treatment and understanding of WM.