Table 2.
Overview of trial characteristics
| No. | Primary Author, year of publication | Enrollment period | Patients with HER2-negative status (%) | Hormone receptor-positive status (%) | Double-blinded | Line of therapya | Therapy option (c = combi vs. mono; m = mono vs. mono) | Intervention (study drug vs. control) | Median follow-up | HR OS (95% CI), nA = number of events study drug, nB = number of events control |
HR PFS (95% CI), nA = number of events study drug, nB = number of events control |
|---|---|---|---|---|---|---|---|---|---|---|---|
| (1) |
Bachelot, 2012 [20]b |
March 2008–May 2009 | 95.5 |
100 (ER and/or PR) |
No | 1 + 2 | c | Tamoxifen + everolimus (n = 54) vs. tamoxifen (n = 57) | Tamoxifen + everolimus: 23.7 months (range 2.6–32.7 months), tamoxifen: 24.2 months (range 0.9–36.2 months) | 0.45 (0.24, 0.81), nA = 16, nB = 31 | TTP, 0.54 (0.36, 0.81), nA = NA, nB = NA |
| (2) |
Bergh, 2012 (FACT) [18]b |
January 2004–March 2008 | NAc |
100 (ER and/or PR) |
No | 1 | c | Anastrozole + fulvestrant (n = 258) vs. anastrozole (n = 256) | 8.9 months (range 0–54 months) | 1.00 (0.76, 1.32), nA = 102, nB = 102 | TTP, 0.99 (0.81, 1.20), nA = 200, nB = 200 |
| (3) |
Burstein, 2014 (CALGB 40302) [21]b |
September 2006–July 2010 | 80.8 |
100 (ER and/or PR) |
Yes | 1 + 2 + 3 | c | Fulvestrant + lapatinib (n = 146) vs. fulvestrant + placebo (n = 145) | 33.6 months | 1.10 (0.83, 1.47)d, nA = NA, nB = NA | 0.96 (0.75, 1.22)d, nA = NA, nB = NA |
| (4) |
Clemons, 2014 (ZAMBONEY) [22]b |
October 2009–October 2011 | 95.3 |
100 (ER and/or PR of primary tumor) |
Yes | 1 + 2 + 3 | c | Fulvestrant + vandetanib (n = 61) vs. fulvestrant + Placebo (n = 68) | NA | 0.69 (0.37, 1.31), nA = 18, nB = 23 | 0.94 (0.64, 1.36), nA = 55, nB = 63 |
| (5) |
Di Leo, 2010/2014 (CONFIRM)e [23]b [24]b |
February 2005–August 2007 | NAc |
100 ER |
Yes | 1 + 2 | m | Fulvestrant 500 mg (n = 362) vs. fulvestrant 250 mg (n = 374) | NA | 0.79 (0.67, 0.94), nA = 261, nB = 293 | 0.79 (0.68, 0.93)f, nA = 297, nB = 321 |
| (6) |
Dickler, 2016 (CALGB 40503) [19]b |
May 2008–November 2011 | 90.7 |
100 (ER and/or PR) |
Yes | 1 + 2 | c | Letrozole + bevacizumab (n = 173) vs. letrozole + Placebo (n = 170) | 39 months for PFS, 42 months for OS | 0.87 (0.65, 1.18), nA = 81, nB = 90 | 0.75 (0.59, 0.96), nA = 126, nB = 138 |
| (7) |
Finn, 2015 (PALOMA-1) [25]b |
December 2009–May 2012 | 100 |
100 (ER) |
No | 1 | c | Letrozole + palbociclib (n = 84) vs. letrozole (n = 81) | Letrozole + palbociclib: 29.6 months (95% CI 27.9–36.0), letrozole: 27.9 months (95% CI 25.5–31.1) | 0.81 (0.49, 1.34), nA = 30, nB = 31 | 0.49 (0.32, 0.75), nA = 41, nB = 59 |
| (8) |
Iwata, 2013 [26]b |
April 2005–December 2010 | ~86.6c |
88.66 (ER and/or PR) |
Yes | 1 | m | Exemestane (n = 147) vs. anastrozole (n = 145) | NA | 1.06 (0.73, 1.54), nA = 57, nB = 55 | TTP, 1.01 (0.77, 1.32), nA = 103, nB = 114 |
| (9) |
Johnston, 2013 (SoFEA)g [27]b |
March 2004–August 2010 | ~86.6h |
99.6% (ER and/or PR) |
Yes (anastrozole and placebo) | 1 + 2 | c | Fulvestrant + anastrozole (n = 243) vs. fulvestrant + Placebo (n = 231) | 37.9 months (interquartile range 23.1–50.8 months) | 0.95 (0.76, 1.17), nA = 168, nB = 167 | 1.00 (0.83, 1.21), nA = 235, nB = 221 |
| (10) |
Llombart-Cussac, 2012 [28]b |
September 2001–May 2003 | NAc |
100 (ER and/or PR) |
No | 1 | m | Exemestane (n = 49) vs. Anastrozole (n = 51) | 9.1 months (range, 0.07–79.96 months) | 1.33 (0.78, 2.25), nA = NA, nB = NA | TTP, 1.13 (0.75, 1.72), nA = 44, nB = 44 |
| (11) |
Martin, 2015 (LEA) [29]b |
November 2007–August 2011 | 100 | 100 | No | 1 | c | Letrozole/fulvestrant + bevacizumab (n = 190) vs. letrozole/fulvestrant (n = 184) | 23.7 months (range, 0–58.2 months) | 0.87 (0.58, 1.32), nA = 47, nB = 45 | 0.83 (0.65, 1.06), nA = 128, nB = 135 |
| (12) |
Mehta, 2012i [30]b |
June 2004–July 2009 | 89.3h |
100 (ER and/or PR) |
No | 1 | c | Anastrozole + fulvestrant (n = 349) vs. anastrozole (n = 345) | 35 months (range, 3–78) for PFS | 0.81 (0.65, 1.00), nA = 154, nB = 176 | 0.80 (0.68, 0.94), nA = 268, nB = 297 |
| (13) |
Piccart, 2014 (BOLERO-2) [31]b |
June 2009 – January 2011 | 100 |
100 (ER and/or PR) |
Yes | 1 + 2 | c | Exemestane + everolimus (n = 485) vs. exemestane + placebo (n = 239) | NA | 0.89 (0.73, 1.10), nA = 267, nB = 143 | 0.45 (0.38, 0.54), nA = NA, nB = NA |
| (14) |
Robertson, 2013 [32]b |
March 2008–July 2009 | 94.9 |
100 (ER and/or PR) |
Yes (ganitumab/placebo) | 1 + 2 | c | Exemestane/fulvestrant + ganitumab (n = 106) vs. exemestane/fulvestrant + placebo (n = 50) | NA | 1.78 (1.06, 2.98)j, nA = 63, nB = 19 | 1.17 (0.80, 1.72)j, nA = NA, nB = NA |
| (15) |
Yamamoto, 2013 [33]b |
October 2008–November 2011 | 91.2 |
100 (ER and/or PR) |
No | ≥ 2 | m | Toremifene (n = 46) vs. exemestane (n = 45) | NA | 0.60 (0.26, 1.39), nA = NA, nB = NA | 0.61 (0.38, 0.99), nA = NA, nB = NA |
| (16) |
Yardley, 2013 [34]b |
June 2008–July 2010 | 90.8 |
98.5% (ER) 78.5% (PR) |
Yes |
≥ 1 NA |
c | Exemestane + entinostat (n = 64) vs. exemestane + placebo (n = 66) | Exemestane + entinostat: 24.0 months, exemestane + placebo 26.4 months, for OS, respectively | 0.59 (0.36, 0.97), nA = NA, nB = NA | 0.73 (0.50, 1.07), nA = NA, nB = NA |
CI confidence interval, HR hazard ratio of interventional study drug vs. control, NA not available
aLine of therapy for locally advanced or metastatic disease, previous therapy included endocrine and/or chemotherapy
bPublication reporting hazard ratio for relevant endpoints
cAccording to registry data, a proportion of 81.9% of the hormone receptor-positive patients was assumed to be HER2-negative in case HER2 status was unknown [13]. For patients with both unknown HER2 status and hormone receptor status, a proportion of 64.5% was assumed to be hormone receptor-positive and HER2-negative [13]
dRecalculated hazard ratio for lapatinib vs. placebo. Burstein, 2014 originally reported inverse effect measures of placebo to lapatinib: OS HR: 0.91; 95% CI: 0.68-1.21, PFS HR: 1.04; 95% CI: 0.82-1.33
eCONFIRM results for endpoint OS are published by Di Leo, 2010 and results for endpoint PFS are published by Di Leo, 2014
fCorrected HR and CI used for analyses [23]
gSoFEA also examined third treatment arm exemestane and compared fulvestrant + placebo vs. exemestane which is not included in STE analysis
hStudy included both patients with known HER2 status as well as patients with unknown HER2 status (hormone receptor status of patients positive for both groups). For the latter group of patients, 81.9% was assumed to be HER2-negative; see footnote (d)
iMehta, 2012 reported comparison of anastrozole vs. anastrozole + fulvestrant. To be consistent with other trials in the study pool comparing a combination therapy with a mono therapy, we calculated inverse hazard ratios to represent the comparison of anastrozole + fulvestrant vs. anastrozole
jRecalculated 95% CI to be consistent with other results of this table. Robertson, 2013 originally reported 80% CI for OS (HR 1.78, 80% CI 1.27–2.50; p = 0.025) and PFS (HR 1.17, 80% CI 0.91–1.50; p = 0.44)