NE Oncology Issue – May 2014

Burris H, et al. SABCS 2013:P2-16-17


The BOLERO-2 trial evaluated the oral mammalian target of rapamycin inhibitor, everolimus (EVE), in combination with the steroidal aromatase inhibitor, exemestane (EXE), in postmenopausal women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer (BC) whose disease relapsed or progressed following a nonsteroidal aromatase inhibitor (NSAI). The results demonstrated that combining EVE + EXE more than doubled median progression-free survival (PFS) compared with placebo plus exemestane (PBO + EXE) without compromising patients’ quality of life. Patients also achieved responses per Response Evaluation Criteria in Solid Tumors (RECIST) during treatment with EVE + EXE. At SABCS 2013, Burris and colleagues presented the analysis of the secondary endpoints from the BOLERO-2 trial.1

Study design

  • BOLERO-2 was a multicentre, international, doubleblind, randomized, phase III trial.
  • Inclusion criteria allowed:
    • Disease recurrence during or ≤12 months after completing adjuvant endocrine therapy;
    • One line of prior chemotherapy for advanced BC;
    • Disease progression within one month after treatment for advanced BC.
  • Patients received open-label EXE 10 mg/day and were randomly assigned 2:1 to either EVE 25 mg/ day or PBO.
    • Randomization was stratified according to the presence of visceral metastasis (yes vs. no) and sensitivity to previous hormonal therapy (yes vs. no).
  • Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal.
    • No crossover was allowed after disease progression.
  • The primary endpoint was PFS by local assessment, defined as the time from randomization to first documented progression or death from any cause.
  • Secondary endpoints included:
    • Overall response rate (ORR; complete response [CR] or partial response [PR]);
    • Clinical benefit rate (best response of CR, PR, or stable disease ≥24 weeks);
    • Time to response (TTR; from date of randomization until first documented response); and
    • Duration of overall response (DOR) for patients with a CR or PR (from documented response to documented progression or disease-related death).
  • In addition, best percentage change from baseline in the sum of the longest diameters of target lesions was assessed.
  • Tumours were evaluated by RECIST version 1.0 based on investigator assessment (local radiologic assessment) and supported by independent radiology committee (central radiologic assessment)
  • Adverse events (AEs) were monitored continuously throughout the study and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.


Key findings

  • Patient characteristics at baseline were well balanced between the two treatment groups.
    • A broad range of the HR+ advanced BC disease spectrum was represented.
    • The majority of patients had ≥2 metastatic sites.
  • The objective response rate by local tumour assessment at the 18-month median follow-up was significantly higher in the EVE + EXE group compared with the PBO + EXE group (12.6% [n = 61] vs. 1.7% [n = 4], respectively; p <0.0001). (Figure 1)
    • The objective response rate was confirmed by central radiology review (12.6% [n = 61] vs. 2.1% [n = 5], respectively).
  • The median DOR by Kaplan-Meier estimate was 10.5 months (95% CI: 8.2–21.9 months) for the EVE + EXE group and 6.9 months (95% CI: 4.2–6.9 months) for the PBO + EXE group. (Figure 2)
    • Median DOR was approximately 3.6 months longer in the EVE + EXE group than in the PBO + EXE group.
  • The overall median TTR could not be calculated using the Kaplan-Meier method in the overall population because the proportion of patients who had a tumour response in each treatment group was low. (Figure 3)
    • Among the subgroup of patients with a CR or PR, the median TTR was 2.8 months (range, 1.2–19.4 months) in the EVE + EXE group and 5.0 months (range, 1.3–12.2 months) in the PBO + EXE group.
  • Decreases from baseline in the sum of the longest target lesion diameters by local assessment were shown among the following subgroups of patients:
    • Patients with measurable disease: 71% of evaluable patients in the EVE + EXE group (n = 318 patients with valid data) and 30% of evaluable patients in the PBO + EXE group (n = 155 patients with valid data) had tumour reduction. (Table 1)
    • Patients with baseline visceral disease: 69% of these patients in the EVE + EXE group (n/N = 224/271 patients with valid data) and 27% of these patients in the PBO + EXE group (n/N = 107/135 patients with valid data) had tumour reduction.
    • Patients who had neoadjuvant and/or adjuvant treatment as last prior therapy: 79% of these patients in the EVE + EXE group (n/N = 62/100 patients with valid data) and 30% of these patients in the PBO + EXE group (n/N = 23/37 patients with valid data) had tumour reduction.

Key conclusions

  • The combination of EVE + EXE significantly improved the ORR compared with PBO + EXE in patients with HR+,
    HER2– advanced BC progressing during or after NSAI therapy.

    • Greater than two-thirds of patients treated with EVE + EXE experienced tumour shrinkage during treatment.
    • Tumour shrinkage was also observed with EVE + EXE treatment in subsets of patients with visceral metastases at baseline or patients who had neoadjuvant and/or adjuvant therapy as their last treatment before study entry.
  • Median DOR was longer in patients treated with EVE + EXE (10.5 months) compared with PBO + EXE (6.9 months).
    However, only four patients responded in the PBO + EXE group.
  • These results support combining EVE + EXE to elicit objective response and improve clinical outcomes in HR+,
    HER2– advanced BC recurring/progressing on or after NSAI therapy.

Reference: 1. Burris H, Gnant M, Hortobagyi G, et al. Characterization of response to everolimus in BOLERO-2: a phase III trial of everolimus plus exemestane in postmenopausal women with HR+, HER2– advanced breast cancer. SABCS Abstracts 2013:P2-16-17.

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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.