Table 1.
Characteristics of the randomised controlled trials included in the systematic review
| Trial name/author | Phase | Meno-pausal status | Patients (N)* | Comparisons | Median of ET (N)† | Previous CT | ITT* PFS HR (95% CI) |
ITT* OS HR (95% CI) |
De novo* PFS HR (95% CI) | Recurrent* PFS HR (95% CI) |
Visceral* PFS HR (95% CI) |
Bone-only* PFS HR (95% CI) |
| Endocrine-sensitive patients only | ||||||||||||
| Ibrahim et al11 | II | Post-meno | 110 | AS1402+AI (letrozole) versus AI (letrozole) | 0 | No | 0.95 (0.50 to 1.81) |
– | – | – | – | – |
| SWOG S022612 | III | Post-meno | 536 | Fulvestrant 250 mg+AI (anastrozole) versus AI (anastrozole) | 0 | No | 0.81 (0.67 to 0.98) |
–‡ | – | – | – | – |
| Paul et al‡§13 | II | Post-meno | 120 | MultiTKI (dasatinib)+AI (letrozole) versus AI (letrozole) | 0 | ≤1 line | No HR | – | – | – | – | – |
| PALOMA-114–16 | II | Post-meno | 165 | CDK4/6i (palbociclib)+AI (letrozole) versus AI (letrozole) | 0 | No | 0.49 (0.32 to 0.75) |
0.90 (0.62 to 1.29) |
0.34 (0.19 to 0.60) |
0.54 (0.30 to 0.96) |
0.55 (0.32 to 0.94) |
0.29 (0.09 to 0.95) |
| PALOMA-217–20 | III | Post-meno | 666 | CDK4/6i (palbociclib)+AI (letrozole) versus AI (letrozole) | 0 | No | 0.58 (0.46 to 0.72) |
– | 0.61 (0.44 to 0.85) |
0.58 (0.41 to 0.82) |
0.62 (0.47 to 0.81) |
0.41 (0.26 to 0.63) |
| MONALEESA-221–24 | III | Post-meno | 668 | CDK4/6i (ribociclib)+AI (letrozole) versus AI (letrozole) | 0 | No | 0.56 (0.43 to 0.72) |
0.75 (0.52 1.08) |
0.45 (0.27 to 0.75) |
0.60 (0.45 to 0.81) |
0.54 (0.39 to 0.74) |
0.69 (0.38 to 1.25) |
| FALCON25–27 | III | Post-meno | 462 | Fulvestrant 500 mg versus AI (anastrozole) | 0 | Allowed | 0.80 (0.64 to 0.999) |
0.88 (0.63 to 1.22) |
– | – | 0.99 (0.74 to 1.33) |
– |
| MINT28 | II | Post-meno | 359 | Sapatinib 20 mg+AI (anastrozole) versus Ai | 0 | ≤1 line | 1.37 (0.91 to 2.06) |
– | – | – | – | – |
| Sapatinib 40 mg+AI (anastrozole) versus AI (anastrozole) | 1.16 (0.77 to 1.75) |
|||||||||||
| MONARCH 329 30 | III | Post-meno | 493 | CDK4/6i (abemaciclib)+AI (anastrozole or letrozole) versus AI (anastrozole or letrozole) | 0 | No | 0.54 (0.41 to 0.72) |
– | 0.49 (0.31 to 0.76) |
0.58 (0.42 to 0.81) |
0.61 (0.42 to 0.87) |
0.58 (0.27 to 1.25) |
| MONALEESA-731 32 | III | Pre-meno | 672 | CDK4/6i (ribociclib)+tamoxifen+goserelin§ versus tamoxifen +goserelin§ | 0 | ≤1 line | 0.59 (0.39 to 0.88) |
0.79 (0.45 to 1.38) |
– | – | – | – |
| CDK4/6i (ribociclib)+AI (anastrozole or letrozole)+goserelin versus AI (anastrozole or letrozole)+goserelin | 0.57 (0.44 to 0.74) |
0.70 (0.50 to 0.98) |
||||||||||
| Endocrine-resistant patients only | ||||||||||||
| TAMRAD§33 | II | Post-meno | 111 | Everolimus+tamoxifen versus tamoxifen | NR | ≤1 line | 0.54 (0.36 to 0.81) |
0.45 (0.24 to 0.81) |
– | – | – | – |
| BOLERO-234–38 | III | Post-meno | 724 | Everolimus+AI (exemestane) versus AI (exemestane) | NR | ≤1 line | 0.45 (0.38 to 0.54) |
0.89 (0.73 to 1.10) |
– | – | 0.47 (0.37 to 0.60) |
0.33 (0.21 to 0.53) |
| SoFEA39 | III | Post-meno | 405 | Fulvestrant 250 mg+AI (anastrozole) versus fulvestrant 250 mg | 1 | ≤1 line | 0.95 (0.75 to 1.22) |
0.85 (0.64 to 1.14) |
– | – | – | – |
| Fulvestrant 250 mg versus AI (exemestane) | 1.06 (0.83 to 1.34) |
1.26 (0.95 to 1.66) |
||||||||||
| CALGB 40 30240 | III | Post-meno | 235 | Lapatinib+fulvestrant 250 mg versus fulvestrant 250 mg | NR | ≤1 line | 1.00 (0.76 to 1.30) |
– | – | – | – | – |
| SAKK21/08§41 | II | Post-meno | 43 | Selumetinib+fulvestrant 500 mg versus fulvestrant 500 mg | 1 | ≤1 line | No HR | – | – | – | – | – |
| Adelson et al42 | II | Post-meno | 116 | Bortezomib+fulvestrant 500 mg versus fulvestrant 500 mg | 1 | ≤1 line | 0.73 (0.49 to 1.09) |
– | – | – | – | – |
| PALOMA-320 43–45 | III | Both | 521 | CDK4/6i (palbociclib)+fulvestrant 500 mg versus fulvestrant 500 mg | 1 | ≤1 line | 0.46 (0.36 to 0.59) |
0.81 (0.64 1.03) |
– | – | 0.47 (0.34 to 0.63) |
0.63 (0.38 to 1.06) |
| O'Shaughnessy et al46 | II | Post-meno | 297 | Anti-androgen (abiraterone acetate) versus AI (exemestane) | 1 | ≤1 line | 1.1 (0.82 to 1.60) |
– | – | – | – | – |
| Anti-androgen (abiraterone acetate)+AI (exemestane) versus AI (exemestane) | 0.96 (0.70 to 1.32) |
0.51 (0.32 to 0.80) |
2.09 (1.04 to 4.19) |
|||||||||
| FERGI64 | II | Post-meno | 168 | Pan-PI3Ki (pictilisib)+fulvestrant 500 mg versus fulvestrant 500 mg | 1 | ≤1 line | 0.74 (0.52 to 1.06) |
– | – | – | 0.74 (0.46 to 1.18) |
– |
| BELLE-247 48 | III | Post-meno | 1147 | Pan-PI3Ki (buparlisib)+fulvestrant 500 mg versus fulvestrant 500 mg | 1 | ≤1 line | 0.78 (0.67 to 0.89) |
0.87 (0.74 to 1.02) |
– | – | 0.76 (0.63 to 0.90) |
0.66 (0.46 to 0.95) |
| MONARCH 230 49 | III | Both | 669 | CDK4/6i (abemaciclib)+fulvestrant 500 mg versus fulvestrant 500 mg | 0 | No | 0.55 (0.45 to 0.68) |
0.76 (0.61 to 0.95) |
– | – | 0.48 (0.37 to 0.63) |
0.54 (0.36 to 0.83) |
| Musolino et al50 | II | Post-meno | 97 | MultiTKI (dovitinib)+fulvestrant 500 mg versus fulvestrant 500 mg | NR | No | 0.68 (0.41 to 1.14) |
0.81 (0.39 to 1.65) |
– | – | – | – |
| Zhao et al51 | II | Post-meno | 60 | Meftormin+AI (letrozole or exemestane) versus AI (letrozole or exemestane) | 1 | Allowed | 1.20 (0.7 to 2.1) |
1.10 (0.50 to 2.40) |
– | – | – | – |
| MANTA55 | II | Post-meno | 326 | Vistusertib continuous+fulvestrant 500 mg versus fulvestrant 500 mg | 1 | ≤1 line | 0.88 (0.63 to 1.24) |
– | – | – | – | – |
| Vistusertib intermittent+fulvestrant 500 mg versus fulvestrant 500 mg | 0.79(0.55 to 1.12) | |||||||||||
| Everolimus+fulvestrant 500 mg versus fulvestrant 500 mg | 0.63 (0.42 to 0.92) |
|||||||||||
| Everolimus+fulvestrant 500 mg versus vistusertib continuous+fulvestrant 500 mg | 0.63 (0.45 to 0.90) |
|||||||||||
| Vistusertib continuous+fulvestrant 500 mg versus vistusertib intermittent+fulvestrant 500 mg | 1.11 (0.81 to 1.52) |
|||||||||||
| PrE010252 | II | Post-meno | 130 | Everolimus+fulvestrant 500 mg versus fulvestrant 500 mg | NR | ≤1 line | 0.61 (0.40 to 0.92) |
1.31 (0.72 to 2.38) |
– | – | – | – |
| BELLE-353 | III | Post-meno | 432 | Pan-PI3Ki (buparlisib)+fulvestrant 500 mg versus fulvestrant 500 mg | 2 | Allowed | 0.67 (0.53 to 0.84) |
– | – | – | 0.56 (0.43 to 0.74) |
– |
| KCSG BR10−04/FLAG54 | II | Both | 138 | Fulvestrant 500 mg+goserelin versus goserelin | 0 | Allowed | 0.61 (0.37 to 0.998) |
0.60 (0.28 to 1.32) |
0.73 (0.26 to 2.01) |
– | 0.67 (0.34 to 1.34) |
– |
| AI (anastrozole)+goserelin versus goserelin | 0.98 (0.62 to 1.55) |
0.52 (0.23 to 1.19) |
0.69 (0.24 to 1.96) |
1.04 (0.54 to 1.97) |
||||||||
| ACE56 | III | Post-meno | 365 | Tucidinostat+AI (exemestane) versus AI (exemestane) | NR | ≤1 line | 0.75 (0.58 to 0.98) |
– | – | – | 0.69 (0.50 to 0.96) |
– |
| FAKTION**62 | Capivasertib+fulvestrant 500 mg versus fulvestrant 500 mg | 0.58 (0.39 to 0.84) |
0.59 (0.34 to 1.05) |
|||||||||
| Both endocrine-sensitive and endocrine-resistant patients | ||||||||||||
| EGF3000857 | III | Post-meno | 752 ES 200 ER |
Lapatinib+AI (letrozole) versus AI (letrozole) | NR | No | ES: 0.94 (0.79 to 1.13) ER: 0.78 (0.57 to 1.07) |
– | – | – | – | – |
| Krop et al**58 | II | Post-meno | 127 ES 120 ER |
Anti-androgen (enzalutamide)+AI (exemestane) versus AI (exemestane) | NR | ≤1 line | ES: 0.82 (0.54 to 1.26) ER: 1.02 (0.66 to 1.59) |
– | – | – | – | – |
| MONALEESA-359 60 | III | Post-meno | 367 ES 345 ER |
CDK4/6i (ribociclib)+fulvestrant 500 mg versus fulvestrant 500 mg | 0 | No | ES: 0.58 (0.42 to 0.80) |
ES: 0.70 (0.48 to 1.02) |
– | – | – | – |
| 1 | No | ER: 0.57 (0.43 to 0.74) |
ER: 0.73 (0.53 to 1.004) |
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*Only for hormone receptor-positive/HER2-negative patients, without other molecular selection.
†Median number of ET lines for advanced breast cancer.
‡Result was not provided separately for hormone-receptor positive/HER2-negative patients, therefore it was not included in the analysis.
§Arm/trial not included in the network meta-analysis.
¶Results published only in meeting abstracts (without a full publication) at the time of literature search.
AI, aromatase inhibitor; CDK, cyclin-dependent kinase; CDK4/6i, CDK4/6 inhibitor; CT, chemotherapy; ER, endocrine-resistant; ES, endocrine-sensitive; ET, endocrine therapy; ITT, intention-to-treat population; multiTKI, multi-tyrosine kinase inhibitor; NR, not reported; OS, overall survival; pan-PI3Ki, pan-PI3K inhibitor; PFS, progression-free survival; post-meno, post-menopausal patients only; pre-meno, pre-menopausal patients only.