Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis

Breast Cancer Research and Treatment, Jan 2014

Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38–0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45–0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31–0.51 and HR = 0.50; 95 % CrI 0.37–0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38–0.58 and HR = 0.55; 95 % CrI 0.40–0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.

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Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis

Thomas Bachelot 0 1 2 3 4 Rachael McCool 0 1 2 3 4 Steven Duffy 0 1 2 3 4 Julie Glanville 0 1 2 3 4 Danielle Varley 0 1 2 3 4 Kelly Fleetwood 0 1 2 3 4 Jie Zhang 0 1 2 3 4 Guy Jerusalem 0 1 2 3 4 0 K. Fleetwood Quantics, Edinburgh, UK 1 R. McCool S. Duffy J. Glanville D. Varley York Health Economics Consortium, University of York , York, UK 2 T. Bachelot (&) Departement de Cancerologie Medicale, Centre Leon Berard , 28 rue Laennec, 69008 Lyon Cedex 08, France 3 G. Jerusalem Centre Hospitalier Universitaire du Sart Tilman Lie`ge and Lie`ge University , Lie`ge, Belgium 4 J. Zhang Novartis Pharmaceuticals Corporation , East Hanover, NJ, USA Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38-0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45-0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31-0.51 and HR = 0.50; 95 % CrI 0.37-0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38-0.58 and HR = 0.55; 95 % CrI 0.40-0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor. - For patients with hormone-receptor-positive advanced breast cancer, endocrine therapy is the recommended initial treatment, and aromatase inhibitors (AIs) are the preferred option for postmenopausal women because they elicit prolonged disease control compared with tamoxifen [13]. Treatment options for patients who experience disease progression after nonsteroidal AI therapy are limited. Recently, the combination regimen of everolimus, an mTOR inhibitor, and exemestane, a steroidal AI, was approved for use in this setting based on significant improvement of progression-free survival (PFS) versus exemestane alone [4]. Other options include exemestane alone, fulvestrant (an estrogen-receptor down-regulator), megestrol acetate, and chemotherapy [13]. Current guidelines recommend continued endocrine therapy for responsive disease; however, clinical questions regarding optimal sequencing of therapy remain [13]. Exemestane has shown activity in patients with advanced breast cancer as a second- and third-line agent following nonsteroidal AI treatment [5]. In patients who had disease progression after first-line letrozole or anastrozole (n = 249), exemestane provided a clinical benefit rate of 27 % with a median PFS of 3.4 months [5]. Even after two prior endocrine treatments in the advanced breast cancer setting (n = 60), exemestane demonstrated a clinical benefit rate of 38 % [6]. Robust clinical evidence favoring the use of everolimus plus exemestane rather than exemestane alone was demonstrated in BOLERO-2, a phase 3 study in postmenopausal women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer progressing/recurring on/after nonsteroidal AI treatment [4, 7]. In this study, median PFS was more than doubled in the everolimus plus exemestane group (7.8 months vs 3.2 for exemestane alone, by local assessment; hazard ratio [HR] = 0.45; P \ 0.0001). Central assessment of median PFS confirmed the clinical benefit with everolimus plus exemestane (11.0 months vs 4.1 for exemestane alone; HR = 0.38; P \ 0.0001). In addition, PFS benefits were consistent across patient subgroups defined by age, race, presence of visceral metastases, and prior chemotherapy. A clinical trial of fulvestrant 250 mg in postmenopausal women with hormone-receptor-positive advanced breast cancer progressing on nonsteroidal AI treatment showed a similar duration of disease control as with exemestane (median time to progression [TTP] = 3.7 mont (...truncated)


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Thomas Bachelot, Rachael McCool, Steven Duffy, Julie Glanville, Danielle Varley, Kelly Fleetwood, Jie Zhang, Guy Jerusalem. Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis, Breast Cancer Research and Treatment, 2014, pp. 125-133, Volume 143, Issue 1, DOI: 10.1007/s10549-013-2778-5