Introduction
Methods
Data sources
Inclusion and exclusion criteria
Data extraction and quality assessment
Statistical analysis
Results
Characteristics of the included studies
Author, year | Trail name | Pathway inhibitor | Phase Status | Intervention group(n) | Control group(n) | Patients | Outcomes* |
---|---|---|---|---|---|---|---|
Dennis J. Slamon, 2018 | MONALEESA-3 | CDK4/6 inhibitor | Phase III | ribociclib plus fulvestrant(n = 484) | placebo plus fulvestrant(n = 242) | Postmenopausal women and men with histologically and/or cytologically confirmed HR-positive/HER2-negative advanced breast cancer | 1,2,3,5 |
Massimo Cristofanilli, 2016 | PALOMA3 | CDK4/6 inhibitor | Phase III | palbociclib plus fulvestrant(n = 347) | placebo plus fulvestrant(n = 174) | Confirmed hormone receptor-positive, HER2-negative metastatic breast cancer. Women aged 18 years or older of any menopausal status | 1,2,3,4,5 |
George W. Sledge, 2017 | MONARCH 2 | CDK4/6 inhibitor | Phase III | abemaciclib plus fulvestrant(n = 446) | placebo plus fulvestrant(n = 223) | Women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET) | 1,2,3,4,5 |
Binghe Xu, 2021 | DAWNA-1 | CDK4/6 inhibitor | Phase III | dalpiciclib plus fulvestrant(n = 241) | placebo plus fulvestrant(n = 120) | Women of any menopausal status aged 18–75 years with pathologically confirmed hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer | 1,2,3,4,5 |
José Baselga, 2012 | BOLERO-2 | mTOR inhibitor | Phase III | everolimus plus exemestane(n = 485) | placebo plus exemestane (n = 239) | Patients with hormone-receptor–positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor. | 1,2,3,4,5 |
Noah Kornblum, 2018 | PrE0102 | mTOR inhibitor | Phase II | everolimus Plus fulvestrant (n = 66) | placebo Plus fulvestrant (n = 65) | Postmenopausal women with ER-positive, human epidermal growth factor receptor 2–negative, AI-resistant metastatic breast cancer | 1,2,3,4,5 |
Peter Schmid, 2019 | MANTA | mTOR inhibitor | Phase II | fulvestrant plus vistusertib(n = 103), fulvestrant plus vistusertib(n = 98) fulvestrant plus everolimus(n = 65) | fulvestrant(n = 67) | Patients with estrogen receptor–positive breast cancer progressing after prior aromatase inhibitor treatment | 1,2,3,4,5 |
F. André, E, 2019 | SOLAR-1 | PI3K inhibitor | Phase III | Cohort with PIK3CA-Mutated Cancer: alpelisib plus fulvestrant (n = 169)/Cohort without PIK3CA-Mutated Cancer: alpelisib plus fulvestrant (n = 115) | Cohort with PIK3CA-Mutated Cancer: placebo plus fulvestrant(n = 172)/Cohort without PIK3CA-Mutated Cancer: placebo plus fulvestrant(n = 116) | Men and postmenopausal women who had locally confirmed HR-positive, HER2-negative advanced breast cancer. | 1,2,3,4,5 |
José Baselga, 2017 | BELLE-2 | PI3K inhibitor | Phase III | buparlisib plus fulvestrant(n = 576) | placebo plus fulvestrant(n = 571) | Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment. | 1,2,3,4,5 |
Angelo Di Leo, 2017 | BELLE-3 | PI3K inhibitor | Phase III | buparlisib(n = 289) | placebo(n = 143) | HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors. | 1,2,4,5 |
Ian E Krop, 2016 | FERGI | PI3K inhibitor | Phase II | Part 1: Pictilisib plus fulvestrant (n = 89)/Part 2:Pictilisib plus fulvestrant (n = 41) | Part 1: Placebo plus fulvestrant (n = 79)/Part 2:Placebo plus fulvestrant (n = 20) | Postmenopausal women aged 18 years or older with estrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor. | 1,2,3,5 |
Zefei Jiang, 2019 | ACE | HDAC inhibitor | Phase III | tucidinostat group(n = 244) | placebo group(n = 121) | Postmenopausal women with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy | 1,3,4,5 |
Denise A. Yardley, 2013 | ENCORE301 | HDAC inhibitor | Phase II | entinostat plus exemestane(n = 64) | placebo plus exemestane(n = 66) | Postmenopausal women with ER + advanced breast cancer progressing on a nonsteroidal aromatase inhibitor | 1,2,3,4,5 |
Roisin M. Connolly, 2021 | E2112 | HDAC inhibitor | Phase III | exemestane plus entinostat(n = 305) | exemestane plus placebo(n = 303) | Men or women with advanced HR-positive, HER2-negative breast cancer | 1,2,3,4,5 |
Stephen Chia, 2008 | EFECT | - | Phase III | fulvestrant(n = 351) | exemestane(n = 342) | Postmenopausal women with HR + advanced breast cancer progressing or recurring after nonsteroidal AI | 1,3,4,5 |
Stephen R D Johnston, 2013 | SoFEA | - | Phase III | fulvestrant plus anastrozole(n = 243) | fulvestrant plus placebo(n = 231)exemestane(n = 249) | Postmenopausal women with hormone-receptor-positive breast cancer | 1,2,3,4,5 |
Angelo Di Leo, 2010 | CONFIRM | - | Phase III | fulvestrant 500 mg(n = 362) | fulvestrant 250 mg(n = 374) | Postmenopausal women with estrogen receptor–positive advanced breast cancer | 1,2,3,4,5 |
Network meta-analysis
Fulvestrant 500 mg | 0.87 (0.35,2.15) | 0.40 (0.34,0.48) | 0.37 (0.15,0.91) | 0.30 (0.11,0.81) | 0.62 (0.45,0.86) | 0.61 (0.24,1.57) | 1.33 (0.89,1.97) |
---|---|---|---|---|---|---|---|
1.23 (0.54,2.78) | Exemestane 25 mg | 0.46 (0.18,1.16) | 0.43 (0.12,1.51) | 0.35 (0.23,0.51) | 0.71 (0.27,1.86) | 0.70 (0.53,0.93) | 1.52 (0.67,3.42) |
0.51 (0.38,0.69) | 0.42 (0.18,1.00) | CDK4/6 inhibitor + fulvestrant | 0.92 (0.38,2.28) | 0.75 (0.27,2.03) | 1.54 (1.07,2.23) | 1.51 (0.58,3.95) | 3.28 (2.12,5.07) |
0.55 (0.29,1.04) | 0.45 (0.16,1.27) | 1.07 (0.53,2.16) | mTOR inhibitor + fulvestrant | 0.81 (0.22,3.03) | 1.67 (0.65,4.28) | 1.63 (0.45,5.96) | 3.54 (1.35,9.34) |
0.15 (0.04,0.56) | 0.12 (0.04,0.35) | 0.28 (0.07,1.13) | 0.26 (0.06,1.17) | mTOR inhibitor + exemestane | 2.07 (0.73,5.82) | 2.02 (1.25,3.28) | 4.39 (1.79,10.81) |
0.52 (0.36,0.75) | 0.42 (0.17,1.04) | 1.01 (0.63,1.62) | 0.94 (0.45,1.96) | 3.57 (0.88,14.53) | PI3K inhibitor + fulvestrant | 0.98 (0.36,2.66) | 2.12 (1.28,3.54) |
0.78 (0.29,2.07) | 0.63 (0.37,1.08) | 1.51 (0.54,4.19) | 1.40 (0.44,4.52) | 5.35 (1.61,17.77) | 1.50 (0.52,4.27) | HDAC inhibitor + exemestane | 2.17 (0.92,5.13) |
0.89 (0.49,1.60) | 0.72 (0.41,1.28) | 1.73 (0.90,3.33) | 1.61 (0.67,3.83) | 6.11 (1.81,20.64) | 1.71 (0.85,3.43) | 1.14 (0.52,2.50) | fulvestrant 250 mg |
SUCRA rankings
Treatments | PFS | ORR | CBR |
---|---|---|---|
mTOR inhibitor plus exemestane | 89.5 | 96.3 | 80.3 |
CDK4/6 inhibitor plus fulvestrant | 77.8 | 61.6 | 78.8 |
mTOR inhibitor plus fulvestrant | 77.6 | 57.1 | 86.1 |
HDAC inhibitor plus exemestane | 53.8 | 40.1 | 35.3 |
PI3K inhibitor plus fulvestrant | 49.4 | 84.7 | 64.5 |
Exemestane 25 mg | 26.8 | 9.3 | 7.2 |
Fulvestrant 500 mg | 21.0 | 20.3 | 32.1 |
Fulvestrant 250 mg | 4.1 | 30.5 | 15.7 |
Adverse effects
Common grade ≥ 3 AEs with at least 5% incidence | Drug related SAE (%) | Withdrawal rate (%) | |
---|---|---|---|
MONALEESA-3 | |||
Ribociclib Plus Fulvestrant | Neutropenia 53.4%, Leukopenia 14.1% | 11.2 | 4.3 |
Placebo Plus Fulvestrant | 2.5 | 2.1 | |
PALOMA3 | |||
Fulvestrant Plus Palbociclib | Neutropenia 62% | 9.6 | 4 |
Placebo Plus Fulvestrant | - | 14.4 | 2 |
MONARCH 2 | |||
Fulvestrant Plus Abemaciclib | Diarrhea 13.3%, neutropenia 26.5%, anemia 7.2%, Leukopenia 8.8% | 8.8 | 15.9 |
Placebo Plus Fulvestrant | - | 1.3 | 3.1 |
DAWNA-1 | |||
Dalpiciclib Plus Fulvestrant | Neutropenia 84.2%, Leukopenia 62.1%, Thrombocytopenia 5.8%, Lymphopenia 5% | 5.8 | 2.5 |
Placebo Plus Fulvestrant | - | 6.7 | 3.3 |
BOLERO-2 | |||
Exemestane Plus Everolimus | Stomatitis 8%, anemia 6%, | 13.1 | - |
Exemestane | - | 1.7 | - |
PrE0102 | |||
Fulvestrant Plus Everolimus | Oral mucositis 11%, Fatigue 6%, Pneumonitis 6% | - | 9 |
Fulvestrant Plus Placebo | Fatigue 5% | - | 9 |
MANTA | |||
Fulvestrant Plus Daily Vistusertib | stomatitis 13.0%, rash 20.7%, infection 5.4% | - | 17.8 |
Fulvestrant Plus Intermittent Vistusertib | asthenia 5.4%, diarrhea 5.4% | - | 16.8 |
Fulvestrant Plus Everolimus | stomatitis 11.7%, asthenia 5.4%, diarrhea 5.4%, infection 6.7% | - | 18.8 |
Fulvestrant | - | 9.1 | |
SOLAR-1 | |||
Alpelisib Plus Fulvestrant | Hyperglycemia 36.6%, diarrhea 6.7%, rash 9.9% | 34.9 | 9.5 |
Placebo Plus Fulvestrant | - | 16.7 | 3.5 |
BELLE-2 | |||
Buparlisib Plus Fulvestrant | Hyperglycemia < 16%, Increased ALT 26%, Increased AST 18%, rash < 9%, fatigue 5%, depression 5%, anxiety < 6% | 23 | 39 |
Placebo Plus Fulvestrant | - | 16 | 5 |
BELLE-3 | |||
Buparlisib Plus Fulvestrant | Increased ALT 22%, Increased AST 18%, Hyperglycemia 13%, Hypertension 6% | 22 | - |
Placebo Plus Fulvestrant | - | 16 | - |
FERGI | |||
Pictilisib Plus Fulvestrant | Maculopapular rash 9%, diarrhea 8%, fatigue 8%, ALT concentration increased 5%, rash 7% | 16 | 22 |
Placebo Plus Fulvestrant | - | 13 | 5 |
ACE | |||
Tucidinostat | Neutropenia 51%, leucopenia < 19%, thrombocytopenia 27%, hypertriglyceridemia, hypokalemia < 7%, Increased γ-glutamyl transferase, 5% | 21 | 64 |
Placebo | - | 6 | 74 |
ENCORE301 | |||
Exemestane Plus Entinostat | Fatigue 13%, Nausea 5%, Neutropenia 15%, Vomiting 5% | 16 | 11 |
Exemestane Plus Placebo | - | 12 | 2 |
E2112 | |||
Entinostat | White blood cell decreased 6%, Neutrophil count decreased < 20%, Anemia < 8%, Hypophosphatemia < 14% | 4.4 | 16 |
Placebo | - | 5.1 | 8 |
EFECT | |||
Fulvestrant250 | Injection-site pain 9.8%, hot flashes 8.8%, nausea 6.8%, fatigue 6.3% | 1.1 | 2 |
Exemestane | Hot flashes 11.5%, fatigue 10%, nausea 7.5%, arthralgia 5.6% | 0.6 | 2.6 |
SoFEA | |||
Fulvestrant250 + Anastrozole | - | 14.8 | 2.8 |
Fulvestrant250 | Fatigue 5% | 22 | 3.4 |
Exemestane | Fatigue 5% | 29 | 3.6 |
CONFIRM | |||
Fulvestrant250 | - | 7.2 | 2.2 |
Fulvestrant500 | - | 9.7 | 1.6 |