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)