Table 1 Summary of key studies for the first-line treatment of women with HR+, HER2– or unknown HER2 status mBC

Mouridsen H et al., 2001, 2003 [International Letrozole Breast Cancer Group]^a [18, 19]

• Letrozole 2.5 mg OD [n = 453]

• Tamoxifen 20 mg OD [n = 454]

Results at final 32 mos FU—Letrozole/tamoxifen

TTP = 9.4/6.0 mos; p < 0.0001

OS = 34/30 mos; p = NS

Bonneterre J et al., 2000 [TARGET]^a [20]

• Anastrozole 1 mg OD [n = 340]

• Tamoxifen 20 mg OD [n = 328]

Anastrozole/tamoxifen

p = NS for all

TTP = 8.2/8.3 mos

Nabholtz JM et al., 2000 [the North American trial]^a [21]

• Anastrozole 1 mg OD [n = 171]

• Tamoxifen 20 mg OD [n = 182]

Anastrozole/tamoxifen

TTP = 11.1/5.6 mos; p = 0.005

Paridaens RJ et al., 2008 [EORTC BCCG]^a [22]

• Exemestane 25 mg OD [n = 182]

• Tamoxifen 20 mg OD [n = 189]

Exemestane/tamoxifen

PFS = 9.9/5.8 mos; p = 0.028

Robertson JF et al., 2016 [FALCON] [23]

• Fulvestrant 500 mg IM on days 0, 14, and 28, and every 28 days thereafter [n = 230]

• Anastrozole 1 mg OD [n = 232]

Fulvestrant/anastrozole

PFS: 16.6/13.8 mos; p = 0.05

PFS in patients with nonvisceral disease: 22.3/13.8 mos (hazard ratio, 0.59; 95% CI, 0.42–0.84)

Bergh J et al., 2012 [FACT]^a [24]

• Anastrozole 1 mg OD [n = 256]

• Anastrozole 1 mg OD plus fulvestrant 500 mg IM on day 1 and 250 mg on days 15 and 29 of first cycle, and every fourth week thereafter [n = 258]

Fulvestrant + anastrozole/anastrozole

TTP: 10.8/10.2 mos; p = NS

OS: 37.8/38.2 mos; p = NS

Mehta RS et al., 2012, 2019 [SWOG 0226]^b [25, 26]

• Anastrozole 1 mg OD [n = 345]

• Anastrozole 1 mg OD plus fulvestrant 500 mg IM on day 1 and 250 mg on days 14 and 28 of first cycle, and 28 days thereafter [n = 349]

Anastrozole/fulvestrant + anastrozole

All patients

PFS:13.5/15 mos; p = 0.007

Final OS: 42/49.8 mos; p = 0.03

Patients with no prior tamoxifen

PFS:12.6/17 mos; p = 0.006

OS: 40.3/52.2 mos (HR 0.73, 95% CI 0.58–0.92)

Patients with prior tamoxifen

PFS: 14.1/13.5; p = 0.37

OS: 43.5/48.2 mos; p = 0.09

• Letrozole 2.5 mg OD [n = 222]

• Letrozole 2.5 mg OD + palbociclib 125 mg OD for 3 weeks followed by 1 week off [n = 444]

Letrozole + palbociclib/letrozole:

PFS: 24.8/14.5 mos; p < 0.001

Hortobagyi GN et al., 2016, 2018; O Shaughnessy J et al., 2018; Sonke GS et al., 2018 [MONALEESA-2] [28,29,30,31]

• Letrozole 2.5 mg OD + Placebo [n = 334]

• Letrozole 2.5 mg OD + ribociclib 600 mg per day on a 3-weeks–on, 1-week–off schedule in 28-day treatment cycles [n = 334]

Letrozole + ribociclib/letrozole + placebo

PFS: 25.3/16.0 mos; p < 0.0001

ORR: 42.5%/28.7%; p = 0.00009

De novo mBC patients

PFS: Not reached/16.4 mos; HR, 0.45; 95% CI 0.27–0.75

Elderly patients (≥65 years)

PFS: Not reached/18.4 mos; HR, 0.608; 95% CI 0.394–0.937

Goetz MP et al., 2015; Goetz MP et al., 2017; Johnston S et al., 2019 [MONARCH-3] [32,33,34]

• Anastrozole 1 mg or letrozole 2.5 mg OD + placebo [n = 165]

• Anastrozole 1 mg or letrozole 2.5 mg OD + abemaciclib 150 mg orally every 12 h till progression [n = 328]

Abemaciclib + NSAI/NSAI + placebo

PFS at interim analysis: Not reached/14.7 mos; p = 0.000021

Final PFS: 28.1/14.7 mos; p = 0.000002

ORR: 61%/45.5%; p = 0.003

Slamon DJ et al., 2018 [MONALEESA-3]^c [35]

• Ribociclib 600 mg per day on a 3-weeks–on, 1-week–off schedule in 28-day treatment cycles + fulvestrant 500 mg IM on day 1 of each 28-day cycle, with an additional dose on day 15 of cycle 1 [total, n = 484; first-line setting, n = 238]

• Fulvestrant + placebo [total, n = 242; first-line setting, n = 129]

Ribociclib + fulvestrant/fulvestrant + placebo:

Overall PFS (first-line settings): 33.6/19.2 mos; HR 0.546, 95%CI 0.415–0.718

OS (first-line settings): Not reached/45.1 mos; HR 0.700, 95% CI 0.479–1.021

Tripathy D et al., 2018; Im SA et al., 2019 [MONALEESA-7]^c [36]

• Ribociclib 600 mg per day on a 3-weeks–on, 1-week–off schedule in 28-day treatment cycles + oral tamoxifen (20 mg/day)/NSAI + goserelin [total, n = 335; first-line setting, n = 208]

• Placebo + oral tamoxifen (20 mg/day)/NSAI + goserelin [total, n = 337; first-line setting, n = 196]

Royce M et al., 2018 [BOLERO-4]^c [37]

• Everolimus 10 mg/day + letrozole 2.5 mg/day [first-line setting, n = 202]

Everolimus + letrozole:

PFS: 22 mos

Beck JT et al., 2014 [Exploratory analysis of BOLERO-2] [38]

• Everolimus 10 mg OD + exemestane 25 mg OD [n = 100]

• Exemestane 25 mg OD [n = 37]

Everolimus + exemestane/exemestane:

PFS: 11.5/4.1 mos

PFS [according to central assessment]: 15.2/4.2 mos