NE Oncology Issue – April 2013

Swain S, et al. SABCS 2012:P5-18-26


The CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study randomized patients with human epidermal growth factor receptor 2 (HER2)- positive first-line metastatic breast cancer (MBC) to treatment with docetaxel and trastuzumab with or without pertuzumab. The primary end point of independently reviewed progression-free survival (PFS) was significantly prolonged by 6.1 months with the addition of pertuzumab.1 An interim analysis of overall survival (OS) also showed a strong trend in favour of pertuzumab, but the results were immature. After a longer follow-up, Swain et al. conducted a second interim OS analysis and presented the results at SABCS 2012.2 These results represent the final and confirmatory analysis for OS.

Study design

  • CLEOPATRA is a randomized, double-blind, placebo-controlled, phase III trial (NCT00567190).
  • Patients (N = 808) with centrally confirmed HER2- positive MBC were enrolled in this study.
  • Patients received one of two treatment regimens:
    • Pertuzumab plus trastuzumab and docetaxel (pertuzumab arm); or
    • Placebo plus trastuzumab and docetaxel (control arm).
  • Study drugs were administered intravenously once every three weeks until disease progression or unmanageable toxicity:
    • Pertuzumab/placebo: 840 mg initial dose, 420 mg subsequent doses;
    • Trastuzumab: 8 mg/kg initial dose, 6 mg/kg subsequent doses;
    • Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated (≥six cycles recommended).
  • Based on the number of OS events observed, the stopping boundary for statistical significance at this analysis was p ≤0.0138. • Subgroup analyses of OS were performed for the stratification factors and other key baseline characteristics.


Key findings

  • At the time of analysis, median follow-up was 30 months and 267 deaths (69% of planned events for the final analysis) had occurred.
  • Kaplan-Meier estimates of OS rates indicated better survival in the pertuzumab arm than the control arm at one year (94% vs. 89%), two years (81% vs. 69%), and three years (66% vs. 50%). (Figure 1)
  • Analysis of OS showed a statistically significant improvement in favour of the pertuzumab arm (HR = 0.66 [95% CI: 0.52–0.84], p = 0.0008), which provided a 34% reduction in the risk of death. Since the OS analysis achieved statistical significance, it was considered the confirmatory OS analysis. (Figure 1)
  • Time to median OS was 37.6 months in the control arm; median OS had not been reached in the pertuzumab arm. (Figure 1)
  • The pertuzumab arm provided a consistent survival benefit in all but one predefined patient subgroup (patients with nonvisceral disease). (Figure 2)
  • An exploratory analysis of updated investigator-assessed PFS was consistent with results from the primary analysis, showing pertuzumab prolonged PFS by 6.3 months.
  • The median time on study treatment was longer for patients in the pertuzumab arm compared with patients in the control arm (17.4 vs. 11.4 months) consistent with a longer median PFS, but the exposure to docetaxel was similar in both arms.
  • The majority of patients who discontinued study treatment received subsequent therapy for breast cancer (control arm: 76.9%, pertuzumab arm: 75.5%).
  • Overall, adverse events (AEs) reported at the primary analysis and at this second interim analysis were similar and no new safety concerns were reported with one more year of follow-up.
  • Patients in the pertuzumab arm, compared with the control arm, experienced at least 5% higher incidences of diarrhea, rash, mucosal inflammation, pruritus, febrile neutropenia, and dry skin of all grades. (Table 1)
  • In the pertuzumab arm,the grade ≥3 AEs which occurred at a higher incidence than in the control arm included neutropenia, febrile neutropenia, and diarrhea. (Table 1)
  • Treatment with pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac AEs compared with the control arm. (Table 2)
  • Overall, more patients died in the control arm than in the pertuzumab arm (38.4% vs. 27.7%), with the most common cause being progressive disease.
  • AEs leading to death were rare and balanced between arms, with febrile neutropenia or infections being the most common cause (five patients in each arm).

Key conclusions

  • First-line treatment of patients with HER2-positive MBC with the pertuzumab regimen compared with the control regimen was associated with an improvement in OS, which was both statistically significant and clinically meaningful.
  • These results showed that combined HER2 blockade and chemotherapy using the pertuzumab regimen can be considered a standard of care for patients with HER2-positive MBC in the first-line setting.

Reference 1. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109–19. 2. Swain SM, Kim S-B, Cortés J, et al. Confirmatory overall survival analysis of CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study with pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients with HER2-positive first-line (1L) metastatic breast cancer (MBC). SABCS Annual Meeting Abstracts 2012:P5-18-26.

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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.