Study design and data extraction
We reviewed MEDLINE for English language articles published before June 2016 (date of analysis) that reported CBRs from an RCT assessing fulvestrant 500 mg vs. a comparator monotherapy for the treatment of HR+ ABC in postmenopausal women. Fulvestrant at the 250 mg dose was considered a comparator ET based on previous results that have shown fulvestrant 250 mg to be at least as effective as anastrozole in terms of TTP, objective response, and duration of response in the second-line treatment of patients with ABC [
21].
From the literature review, six RCTs evaluating fulvestrant 500 mg for the treatment of HR+ ABC in postmenopausal women were identified and included in the meta-analysis (Table
1).
Table 1
Study design details and baseline patient treatment characteristics for included trials reporting on postmenopausal women with HR+ locally advanced or metastatic breast cancer
Study design |
Phase III, randomized, double-blind, multicenter study in postmenopausal women with ER+ and/or PgR+ locally advanced or metastatic breast cancer (NCT01602380) | Phase II, randomized, open-label, multicenter, parallel-group study in postmenopausal women with ER+ and/or PgR+ ABC (NCT00274469) | Phase III, randomized, double-blind, multicenter, parallel-group study in postmenopausal women with ER+ ABC (NCT00099437) | Phase II, randomized, double-blind, parallel-group study, conducted in Japan, in postmenopausal women with ER+ ABC (NCT00305448) | Phase II, randomized, double-blind, parallel-group, international study in postmenopausal women with ER+ ABC (NCT00313170) | Phase III, randomized, double-blind study, conducted in China in postmenopausal women with ER+ ABC (NCT01300351) |
Treatment arms (number of randomized patients) |
Fulvestrant 500 mg (n = 230) vs. anastrozole 1 mg (n = 232) | Fulvestrant 500 mg (n = 102) vs. anastrozole 1 mg (n = 103) | Fulvestrant 500 mg (n = 362) vs. fulvestrant 250 mg (n = 374) | Fulvestrant 500 mg (n = 47) vs. fulvestrant 250 mg (n = 45) | Fulvestrant 500 mg (n = 46) vs. fulvestrant 250 mg (n = 47) | Fulvestrant 500 mg (n = 111) vs. fulvestrant 250 mg (n = 110) |
Treatment line |
First-line Patients were not permitted to have received prior hormone therapy for breast cancer | First-line Prior ET for advanced disease was not permitted Patients could have received adjuvant ET for early disease, if completed > 12 months before randomization | First- and second-line Patients may have experienced relapse on adjuvant ET or < 1 year from completion of adjuvant ET | Second-line Patients may have relapsed during, or ≤ 12 months after, adjuvant ET, or may be progressing on ET started ≥ 12 months after prior adjuvant ET or for de novo advanced disease | Second-line Patients may have relapsed during or ≤ 12 months after adjuvant ET, or may be progressing on ET started ≥ 12 months after prior adjuvant ET or for de novo advanced disease | First- and second-line Patients may have relapsed during or ≤ 12 months after adjuvant ET, or may be progressing on ET started ≥ 12 months after prior adjuvant ET or for de novo advanced disease |
Median age (range), years |
64 (38–87) vs. 62 (36–90) | 66 (40–89) vs. 68 (48–87) | 61 (NR) vs. 61 (NR) | 61 (45–83) vs. 61 (50–77) | 67 (49–85) vs. 63 (42–88) | 55 (26–80) vs. 55 (31–76) |
Visceral involvement, % |
59 vs. 51 | 47.1 vs. 56.3 | 66 vs. 62 | 57.4 vs. 57.8 | 80.4 vs. 72.3 | NR |
Prior ET, % |
1 vs. < 1 | 28.4 vs. 22.3 | 100 vs. 100 | 100 vs. 100 Anastrozole: 57.4 vs. 57.8 Tamoxifen: 48.9 vs. 42.2 Exemestane: 17.0 vs. 20.0 | Anastrozole: 37.0 vs. 38.3 Tamoxifen: 58.7 vs. 59.6 Exemestane: 34.8 vs. 23.4 | Adjuvant: 97.3 vs. 93.6 Advanced disease: 31.5 vs. 27.3 |
Prior chemotherapy (advanced disease), % |
16 vs. 19 | 0 vs. 0 | | 70.2 vs. 55.6 | 56.5 vs. 59.6 | 22.5 vs. 18.2 |
These were the Fulvestrant and AnastrozoLe COmpared in hormonal therapy-Naïve ABC study (FALCON, NCT01602380), a phase III, randomized, double-blind, double-dummy, international trial comparing fulvestrant 500 mg (days 0, 14, 28, then every 28 days thereafter) with anastrozole 1 mg once daily (QD) in the first-line setting [
9]; the Fulvestrant fIRst-line Study comparing endocrine Treatments (FIRST, NCT00274469), a phase II international trial comparing fulvestrant 500 mg (days 0, 14, 28, then every 28 days thereafter) with anastrozole 1 mg QD in the first-line setting [
10‐
12]; COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM, NCT00099437), a phase III international trial comparing fulvestrant 500 mg (days 0, 14, 28, then every 28 days thereafter) with fulvestrant 250 mg (days 0, 14, 28, then every 28 days thereafter) in the first- and second-line settings [
13,
14]; Faslodex INvestigation of Dose evaluation in Estrogen Receptor-positive ABC (FINDER1, NCT00305448), a phase II trial, conducted in Japan, that compared fulvestrant 500 mg (days 0, 14, 28, then every 28 days thereafter) with fulvestrant 250 mg (250 mg fulvestrant on days 0, 28, then every 28 days thereafter, with placebo injections given on day 14) and fulvestrant loading dose (initial dose of 500 mg fulvestrant at day 0 and 250 mg fulvestrant and placebo on days 14, 28, then every 28 days thereafter) in the second-line setting [
22]; FINDER2 (NCT00313170), a phase II trial, conducted in Canada and Europe, that compared fulvestrant 500 mg (days 0, 14, 28, then every 28 days thereafter) with fulvestrant 250 mg (250 mg fulvestrant on days 0 and 28 and every 28 days thereafter, with placebo injections given on day 14) and fulvestrant loading dose (initial dose of 500 mg fulvestrant at day 0 and 250 mg fulvestrant and placebo on days 14, 28, then every 28 days thereafter) in the second-line setting [
23]; and China CONFIRM (NCT01300351), a phase III trial, conducted in China, that compared fulvestrant 500 mg (days 0, 14, 28, then every 28 days thereafter) with fulvestrant 250 mg (days 1, 28, and every 28 days thereafter, with placebo injections given on day 14) in the first- and second-line settings [
20].
One additional study—the phase II, randomized, open-label Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors (NEWEST, NCT00093002) study [
24] of fulvestrant 500 mg vs. fulvestrant 250 mg—was excluded from the meta-analysis, as the study duration was only 16 weeks and tumor responses were not assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria.
The CBR for each therapy arm in the studies was calculated as the proportion of all randomized patients experiencing a best overall response of complete response or partial response, or a best objective response of stable disease for ≥ 24 weeks. Response subcategories were defined according to RECIST v1.1 criteria [
25].
Complete response was defined as the disappearance of all target lesions and non-target lesions, with no new lesions observed, whereas partial response was considered a > 30% decrease in the sum of diameters of target lesions (compared with baseline), with no progression of non-target lesions and no new lesions. Patients with stable disease had neither sufficient shrinkage of target lesions (i.e., 30% shrinkage) to qualify as a partial response, nor sufficient growth (i.e., 20% increase in the sum of longest diameter of the target lesions, compared with previous smallest sum) to qualify as progression, with no evidence of progression of non-target lesions and no new lesions.
Patients with non-measurable disease at baseline were classed at follow-up as having experienced disease progression if there was evidence of new lytic bone lesions, new lesions outside of the bone, or unequivocal progression of existing bone lesions.
In all studies, patients provided written informed consent and study approval was obtained from independent ethics committees at every study centre. Each study was undertaken in accordance with local legal and regulatory requirements and the general principles of the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the International Conference on Harmonisation guidelines on Good Clinical Practice, and the Declaration of Helsinki.
Statistical analyses
The Peto method was used to calculate odds ratios (OR), 95% confidence intervals (CI), and corresponding
p-values [
26]. The Peto method for pooled ORs is an alternative to the Mantel–Haenszel method [
27]. It is more robust to missing data than the Mantel–Haenszel method when effect sizes are small and can only be used when within-study group sizes are similar and effect sizes are not large [
26]. In this meta-analysis, the application of either the Mantel–Haenszel method or the Peto method would be inconsequential.
Unadjusted OR for CBR for fulvestrant vs. comparator was used in the FALCON, FIRST, CONFIRM, FINDER1, and FINDER2 studies. Adjusted OR was used in China CONFIRM, owing to the stratified randomization scheme used in that study [
20]. Due to the different doses of fulvestrant used, data for the fulvestrant loading dose (initial dose of 500 mg fulvestrant at day 0, and 250 mg fulvestrant and placebo on days 14, 28, then every 28 days thereafter) in the FINDER1 and FINDER2 studies were not included in the analysis. An OR for CBR > 1.0 was considered to favor fulvestrant vs. comparator, an OR of 1.0 indicated no difference between treatments, and an OR < 1.0 was considered to favor the comparator over fulvestrant.
Fixed effects (FE) models were constructed for first- and second-line data, alone and combined. For each model, a Tarone’s test for heterogeneity was used to assess the assumption of constant trial effect [
28]. OR for CBR with fulvestrant 500 mg vs. comparator treatments, and corresponding 95% CI, were calculated.