Safety of Everolimus Plus Exemestane In Patients With Hormone-Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer Progressing on Prior Non-Steroidal Aromatase Inhibitors: Primary Results of a Phase 3b, Open-Label, Single-Arm, Expanded-Access Multicenter Trial (BALLET).
Jerusalem, Guy; Mariani, G.; Ciruelos, E. M.et al.
BMI; advanced breast cancer; elderly, everolimus; hormone-receptor positive; stomatitis; oncology
Abstract :
[en] BACKGROUND: This European phase 3b, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2. PATIENTS AND METHODS: Postmenopausal women aged (3)18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors (NSAIs) were enrolled. Primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). Secondary objective was to evaluate AEs of grade 3/4 severity. RESULTS: Median treatment duration was 5.1 months (95% CI, 4.8-5.6) for EVE and 5.3 months (95% CI, 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AE were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly ((3)70 years) versus non-elderly patients (23.8% vs. 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post-hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related. CONCLUSIONS: This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2. CLINICAL TRIAL REGISTRATION: EudraCT Number: 2012-000073-23.
Disciplines :
Oncology
Author, co-author :
Jerusalem, Guy ; Université de Liège > Département des sciences cliniques > Oncologie
Safety of Everolimus Plus Exemestane In Patients With Hormone-Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer Progressing on Prior Non-Steroidal Aromatase Inhibitors: Primary Results of a Phase 3b, Open-Label, Single-Arm, Expanded-Access Multicenter Trial (BALLET).
Publication date :
29 June 2016
Journal title :
Annals of Oncology
ISSN :
0923-7534
eISSN :
1569-8041
Publisher :
Oxford University Press, United Kingdom
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Cardoso F, Costa A, Norton L et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol 2014; 25(10): 1871-1888.
Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18(22): 3758-3767.
Mouridsen H, Gershanovich M, Sun Y et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21(1): 2101-2109.
Bergh J, Jonsson P-E, Lidbrink EK et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012; 30(16): 1919-1925.
Chia S, Gradishar W, Mauriac L et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008; 26(10): 1664-1670.
Osborne KC, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011; 62: 233-247.
Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med 2012; 366(6): 520-529.
Turner NC, Ro J, Andre F et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015; 373(3): 209-219.
Gnant M. The role of mammalian target of rapamycin (mTOR) inhibition in the treatment of advanced breast cancer. Curr Oncol Rep 2013; 15(1): 14-23.
Jerusalem G, Rorive A, Collignon J. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes. Breast Cancer 2014; 6: 43-57.
Jerusalem G, Bachelot T, Neven P et al. A new era of improving progression-free survival with dual blockade in postmenopausal HR(+), HER2(-) advanced breast cancer. Cancer Treat Rev 2015; 4(2): 94-104.
Gnant M. Overcoming endocrine resistance in breast cancer: importance of mTOR inhibition. Expert Rev Anticancer Ther 2012; 12(12): 1579-1589.
Buolay A, Rudloff J, Ye J et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005; 11(14): 5319-5328.
Yardley DA, Noguchi S, Burris HA et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progressionfree survival analysis. Adv Ther 2013; 30(10): 870-884.
Piccart M, Hortobagyi GN, Campone M et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol 2014; 25(12): 2357-2362.
Pritchard KI, Burris HA, Ito Y et al. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clin Breast Cancer. 2013; 13(6): 421-432.e8.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V1. 2015.