Significant progress has been made in recent years for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). |
In the first-line setting, fulvestrant alone or in combination with an aromatase inhibitor (AI) has been shown to be superior to an AI alone, whereas combinations of endocrine therapy (ET) plus a cyclin-dependent kinase (CDK)4/6 inhibitor has increasingly become the new standard of care. |
Combinations of ET plus CDK4/6 or mammalian target of rapamycin inhibitors have been approved in the ET-resistant setting. |
Recent approval of alpelisib with fulvestrant in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutated HR+, HER2− MBC following progression on or after ET marks the first combination therapy approved based on somatic mutations in MBC. |
The role for genomic biomarkers in guiding individualized treatment of HR+, HER2− MBC is expanding. |
Digital Features
Introduction
ET in the Treatment of HR+, HER2− MBC, Monotherapy Versus Combination Therapy—What do the Data Tell Us?
Fulvestrant as Monotherapy and in Combination with AIs
Study design | Treatment comparison | Patients, n | PFS, months: experimental vs. control arm | Hazard ratio (95% CI) | Median follow-up, months | OS, months: experimental vs. control arm | Hazard ratio (95% CI) | Most common adverse events, %: experimental vs. control arm | |
---|---|---|---|---|---|---|---|---|---|
First-line studiesa | |||||||||
R, DB, PC | Letrozole + palbociclib vs. letrozole + placebo | 666 | 27.6 vs. 14.5 | 0.56 (0.46–0.69) | 37.6 (letrozole + palbociclib) 37.3 (letrozole + placebo) | NA | – | Neutropenia, 79.5 vs. 6.3 Leukopenia, 39.0 vs. 2.3 Fatigue, 37.4 vs. 27.5 Nausea, 35.1 vs. 26.1 | |
R, DB, PC | Letrozole + ribociclib vs. letrozole + placebo | 668 | 25.3 vs. 16.0 | 0.57 (0.46–0.70) | 26.4 | NR vs. 33.0 months | 0.75 (0.52–1.08) | Neutropenia, 74.3 vs. 5.2 Nausea, 51.5 vs. 28.5 Infections, 50.3 vs. 42.4 Fatigue, 36.5 vs. 30.0 | |
R, DB, PC | Fulvestrant + ribociclib vs. fulvestrant + placebo | 726 | 20.5 vs. 12.8 | 0.59 (0.48–0.73) | NA | NR vs. 40.0g | 0.72 (0.57–0.92) | Neutropenia, 69.6 vs. 2.1 Nausea, 45.3 vs. 28.2 Fatigue, 31.5 vs. 33.2 Diarrhea, 29.0 vs. 20.3 | |
FALCON [15] | R, DB | Fulvestrant vs. anastrozole | 524 | 16.6 vs. 13.8 | 0.8 (0.64–1.00) | NA | NA | 0.88 (0.63–1.22) | Arthralgia, 16.7 vs. 10.3 Hot flush, 11.4 vs. 10.3 Fatigue, 11.4 vs. 6.9 Nausea, 10.5 vs. 10.3 |
MONARCH 3 [39] | R, DB, PC | AI + abemaciclib vs. AI + placebo | 493 | NR vs. 14.7 | 0.54 (0.41–0.72) | 17.8 | NA | – | Diarrhea, 81.3 vs. 29.8 Neutropenia, 41.3 vs. 1.9 Fatigue, 40.1 vs. 31.7 Infections and infestations, 39.1 vs. 28.6 |
Second-line studiesa | |||||||||
R, DB, PC | Fulvestrant + palbociclib vs. fulvestrant + placebo | 413 | 9.9 vs. 3.9 | 0.45 (0.34–0.59) | 8.9 | 34.9 vs. 28.0f,g | 0.81 (0.64–1.03)g | Neutropenia, 79.6 vs. 2.9 Infections, 40.1 vs. 29.4 Fatigue, 40.1 vs. 27.9 Nausea, 30.3 vs. 25.0 | |
R, DB, PC | Fulvestrant + abemaciclib vs. fulvestrant + placebo | 669 | 16.4 vs. 9.3 | 0.55 (0.45–0.68) | 19.5 | 46.7 vs. 37.3f | 0.76 (0.61–0.95)g | Diarrhea, 86.4 vs. 24.7 Nausea, 45.1 vs. 22.9 Fatigue, 39.9 vs. 26.9 Neutropenia, 46.0 vs. 4.0 | |
R, DB, PC | Exemestane + everolimus vs. exemestane + placebo | 724 | 7.8 vs. 3.2 | 0.45 (0.38–0.54) | 17.7 | 31.0 vs. 26.6g | 0.89 (0.73–1.10) | Stomatitis, 59 vs. 12 Rash, 39 vs. 7 Fatigue, 37 vs. 27 Diarrhea, 34 vs. 19 | |
R, DB, PC | Fulvestrant + alpelisib vs. fulvestrant + placebo | 572e | 11.0 vs. 5.7 | 0.65 (0.50–0.85) | 20.0 | NR vs. 26.9 | 0.73 (0.48–1.10) | Hyperglycemia, 63.7 vs. 9.8 Diarrhea, 57.7 vs. 15.7 Nausea, 44.7 vs. 22.3 Decreased appetite, 35.6 vs. 10.5 |
ET Combined with CDK4/6 Inhibitors
Study design | Treatment comparison | Patients, n | PFS, months: experimental vs. control arm | Hazard ratio (95% CI) | Median follow-up, months | OS, months: experimental vs. control arm | Hazard ratio (95% CI) | Most common adverse events, %: experimental vs. control arm | |
---|---|---|---|---|---|---|---|---|---|
First-line studya | |||||||||
R, DB, PC | Ribociclib + goserelin + ET or placebo + goserelin + ETb | 672 | 23.8 vs. 13.0 | 0.55 (0.44–0.69) | 19.2 | NR vs. 40.9f | 0.71 (0.54–0.95) | Neutropenia, 75.8 vs. 7.7 Hot flush, 34.0 vs. 33.5 Nausea, 31.6 vs. 19.6 Leukopenia, 31.3 vs. 5.6 | |
Second-line studiesa | |||||||||
R, DB, PC | Fulvestrant + palbociclib vs. fulvestrant + placebo | 108 | 9.5 vs. 5.6 | 0.50 (0.29–0.87) | 8.9 | 34.9 vs. 28.0e,f | 0.81 (0.64–1.03)e | Neutropenia, 85.9 vs. 5.6 Infections, 47.9 vs. 33.3 Nausea, 40.8 vs. 36.1 Leukopenia, 56.3 vs. 2.8 | |
R, DB, PC | Fulvestrant + abemaciclib vs. fulvestrant + placebo | 114 | NR vs. 10.5 | 0.45 (0.26–0.75) | 20.4 (fulvestrant + abemaciclib) 19.6 (fulvestrant + placebo) | 46.7 vs. 37.3 e | 0.76 (0.61–0.95)e | Diarrhea, 87.3 vs. 23.8 Infections and infestations, 43.7 vs. 26.2 Neutropenia, 59.2 vs. 7.1 Headache, 33.8 vs. 31.0 |
AIs in Combination with CDK4/6 Inhibitors
Fulvestrant in Combination with CDK4/6 Inhibitors
Tolerability of CDK4/6 Inhibitors in Combination with ET
ET in Combination with Inhibitors of the PI3K-AKT-mTOR Pathway
ET Combined with mTOR Inhibitors
ET Combined with PI3K Inhibitors
ET Combined with AKT Inhibitors
Treatment Options After Progression on ET Combined with a CDK4/6 Inhibitor
Strategies to overcome resistance mechanisms | Treatment comparison | Clinical development and exploration | Status (phase) | Patient characteristics |
---|---|---|---|---|
ET | Elacestrant (RAD190G1T48) vs. G1T48+ palbociclib | NCT02650817 [76] | Completed (Ib) | Postmenopausal women with ER+, HER2− ABC; progression after ≥ 1 prior line of ET for MBC |
NCT03455270 [77] | Ongoing (I) | Part 2: women with ER+, HER2− ABC; progression on or after adjuvant AI or after prior AI for ABC | ||
ET+ PI3K inhibitor | Fulvestrant + taselisib vs. fulvestrant + placebo | NCT02340221 [67] | Ongoing (III) | Postmenopausal women with HR+, HER2−, PIK3CA mutation-positive ABC; recurrence or progression on or after AI |
Fulvestrant + alpelisib vs. fulvestrant + placebo | NCT02437318 [82] | Ongoing (III) | Men or postmenopausal women with ER+, HER2− ABC and known PIK3CA status; progression on or after ET | |
ET+ CDK4/6 inhibitor ± immunotherapy | Fulvestrant vs. fulvestrant + palbociclib vs. fulvestrant + palbociclib + avelumab | NCT03147287 [68] | Recruiting (II) | Patients with HR+, HER2− ABC; progression on or after ET and CDK4/6 inhibitor |
Pembrolizumab + letrozole + palbociclib | NCT02778685 [69] | Recruiting (II) | Postmenopausal women with newly diagnosed ER+, HER2− MBC | |
ET+ CDK4/6 inhibitor + PI3K or mTOR inhibitor | Ribociclib + everolimus + exemestane | NCT02732119 [70] | Completed (I/II) | Patients with HR+, HER2− ABC; progression on CDK4/6 inhibitor |
Palbociclib + everolimus + exemestane | NCT02871791 [84] | Ongoing (I/II) | Patients with HR+, HER2− MBC; progression on CDK4/6 inhibitor and non-steroidal AI | |
LEE011 + exemestane + everolimus vs. LEE011 + exemestane | NCT01857193 [71] | Completed (I) | Postmenopausal women with HR+, HER2− ABC; progression on or after adjuvant AI or AI for ABC | |
LEE011 + letrozole vs. BYL719 + letrozole vs. LEE011 + BYL719 + letrozole | NCT01872260 [83] | Completed (Ib) | Dose-expansion phase: postmenopausal women with HR+, HER2− ABC; no prior systemic treatment for ABC | |
Abemaciclib in combination therapiesa | NCT02057133 [72] | Ongoing (Ib) | Women with HR+, HER2− MBC; prior systemic ET with ≥ 1 non-steroidal AI for MBC | |
ET ± CDK4/6 or PI3K inhibitor | LSZ102 vs. LSZ102 + LEE011 vs. LSZ102 + BYL719 | NCT02734615 [73] | Recruiting (I) | Patients with HR+, HER2− ABC; progression after ET |
ET+ FGFR inhibitor + CDK4/6 inhibitor | Fulvestrant + erdafitinib + palbociclib | NCT03238196 [74] | Recruiting (Ib) | Men or postmenopausal women with HR+, HER2−, FGFR-amplified MBC; ≥ 1 prior line of therapy for MBC |
ET+ HDAC inhibitor | Exemestane + entinostat vs. exemestane + placebo | NCT02115282 [75] | Ongoing (III) | Patients with HR+, HER2− ABC; relapse or progression on or after non-steroidal AI |
ET+ CDK7 inhibitor | Fulvestrant + SY-1365 | NCT03134638 [86] | Ongoing (I) | Cohort 5: patients with HR+ MBC post CDK4/6 inhibitor and hormonal therapy |
Fulvestrant + CT7001 | NCT03363893 [87] | Recruiting (Ib/II) | Module 2: patients with locally advanced or metastatic HR+ and HER2− BC | |
ET+ aurora A kinase inhibitor | Erbumine + ET | NCT03955939 [88] | Ongoing (I) | Patients with MBC post CDK4/6 inhibitor and ET |
ET+ BCL-2 inhibitor | Fulvestrant + venetoclax vs. fulvestrant | NCT03584009 [85] | Ongoing (II) | Women with ER+, HER2− locally advanced or MBC who experienced disease recurrence or progression during or after CDK4/6 inhibitor |
ET+ immunotherapy | Fulvestrant + pembrolizumab | NCT03393845 [78] | Recruiting (II) | Patients with HR+, HER2− ABC; ≤ 1 prior line of ET (other than fulvestrant) or chemotherapy for ABC |
Pembrolizumab + AI (exemestane, anastrozole, or letrozole) | NCT02648477 [80] | Recruiting (II) | Cohort 2: patients with HR+, HER2− MBC; not resistant to all three approved AIs | |
Pembrolizumab + exemestane + leuprolide | NCT02990845 [79] | Recruiting (I/II) | Pre- or perimenopausal women with HR+, HER2− ABC; resistant to front-line ET | |
ET+ dual immunotherapy | Fulvestrant + durvalumab + tremelimumab | NCT03430466 [81] | Recruiting (II) | Postmenopausal women with HR+, HER2− ABC |