Pan-PI3K inhibitors
|
Buparlisib
|
BELLE-2
Phase III
NCT01610284
[41]
|
HR+/HER2-
Postmenopausal
Locally advanced or MBC
Prior AI treatment
|
Buparlisib + fulvestrant vs. placebo + fulvestrant
|
PFS 6.9 months vs. 5.0 months (HR 0.78; p = 0.00021)
PFS 6.8 months vs. 4.0 months in PI3K mutated (HR 0.76; p = 0.014)
|
BELLE-3
Phase III
NCT01633060
[42]
|
HR+/HER2-
Postmenopausal
Locally advanced or MBC
Prior endocrine therapy or mTOR inhibitors
|
Buparlisib + fulvestrant vs. placebo + fulvestrant
|
PFS 3.9 months vs. 1.8 months (HR 0.67; p = 0.0003)
|
BELLE-4
Phase II/III
NCT01572727
[43]
|
HER2-
Locally advanced or MBC
No prior chemotherapy
|
Buparlisib + pacliatxel vs. placebo + paclitaxel
|
PFS 8.0 months vs. 9.2 months (HR 1.18, 95% CI 0.82–1.68)
PFS 9.1 months vs. 9.2 months in PI3K mutated (HR 1.17, 95% 0.63–2.17)
|
Pictilisib
|
FERGI
Phase II
NCT01437566
[44]
|
HR+/HER2-
Postmenopausal
Prior AI treatment
|
Pictilisib + fulvestrant vs. placebo + fulvestrant
|
PFS 6.6 months vs. 5.1 months (HR 0.74; p = 0.096)
PFS 6.5 months vs. 5.1 months in PI3K mutated (HR 0.74; p = 0.268)
PFS 5.8 months vs. 3.6 months in non-PI3K mutated (HR 0.72; p = 0.23)
|
PEGGY
Phase II
NCT01740336
[45]
|
HR+/HER2-
Locally recurrent
or MBC
|
Pictilisib + paclitaxel vs. placebo + paclitaxel
|
PFS 8.2 months vs. 7.8 months (HR 0.95; p = 0.83)
PFS 7.3 months vs. 5.8 months in PI3K mutated (HR 1.06; p = 0.88)
|
Isoform-specific inhibitors
|
Alpelisib
|
Phase Ib
NCT01791478
[46]
|
HR+/HER2-
Postmenopausal
MBC
Prior endocrine therapy
|
Alpelisib + letrozole
|
CBR 35% (44% in patients with PIK3CA mutated and 20% in PIK3CA wild-type tumors; 95% CI [17%; 56%])
|
SOLAR-1
Phase III
NCT02437318
[47]
|
HR+/HER2-
Advanced BC
Prior endocrine therapy
|
Alpelisib + fulvestrant vs. placebo + fulvestrant
|
PFS 7.4 months vs. 5.6 months in non-PI3K mutated (HR 0.85, 95% CI 0.58–1.25)
PFS 11.0 months vs. 5.7 months in PI3K mutated (HR 0.65; p = 0.00065)
|
NEO-ORB
Phase II
NCT01923168
[48]
|
HR+/HER2-
Postmenopausal
Early-stage BC
Neoadjuvant setting
|
Alpelisib + letrozole vs. placebo + letrozole
|
ORR 43% vs. 45% (PIK3CA mutant), 63% vs. 61% (PIK3CA wildtype)
pCR rates low in all groups
|
Taselisib
|
SANDPIPER
Phase III
NCT02340221
[49]
|
HR+/HER2-
Postmenopausal
Locally advanced or MBC
PIK3CA-mutant
Prior AI treatment
|
Taselisib + fulvestrant vs. placebo + fulvestrant
|
PFS 7.4 months vs. 5.4 months (HR 0.70; p = 0.0037)
|
LORELEI
Phase II
NCT02273973
[50]
|
HR+/HER2-
Postmenopausal
Early-stage BC
Neoadjuvant setting
|
Taselisib + letrozole vs. placebo + letrozole
|
ORR 50% vs. 39.3% (OR 1.55; p = 0.049)
ORR 56.2% vs. 38% in PI3K mutated (OR 2.03; p = 0.033)
No significant difference in pCR
|
mTOR inhibitors
|
Everolimus
|
BOLERO-2
Phase III
NCT00863655
[51]
|
HR+/HER2-
Advanced BC
Prior AI treatment
|
Everolimus + exemestane
vs. placebo + exemestane
|
PFS 6.9 months vs. 2.8 months (HR 0.43; p < 0.001)
|
TAMRAD
Phase II
NCT01298713
[52]
|
HR+/HER2-
Postmenopausal
MBC
Prior AI treatment
|
Everolimus + tamoxifen vs. tamoxifen alone
|
CBR 61% vs. 42%
TTP 8.6 months vs. 4.5 months (HR 0.54)
|
PrE0102
Phase II
NCT01797120
[53]
|
HR+/HER2-
Postmenopausal
MBC
Prior AI treatment
|
Everolimus + fulvestrant
vs. placebo + fulvestrant
|
PFS 10.3 months vs. 5.1 months (HR 0.61; p = 0.02)
CBR 63.6% vs. 41.5% (p = 0.01)
|
Akt inhibitors
|
Capivasertib
|
FAKTION
Phase II
NCT01992952
[54]
|
HR+/HER2-
Postmenopausal
Locally advanced or MBC
Prior AI treatment
|
Capivasertib + fulvestrant vs. placebo + fulvestrant
|
PFS 10.3 months vs. 4.8 months (HR 0.57; p = 0.0035)
|
Phase I
NCT01226316
[55]
|
ER+
AKT1E17K-mutant
MBC
Prior endocrine treatment
|
Capivasertib + fulvestrant vs. Capivasertib alone
|
CBR 50% vs. 47%
ORR 6% (fulvestrant-pretreated) and 20% (fulvestrant-naïve) vs. 20%
|
CDK4/6 inhibitors
|
Palcociclib
|
PALOMA-1
Phase II
NCT00721409
[56]
|
HR+/HER2-
Postmenopausal
Advanced BC
No prior systemic treatment
|
Palbocilib + letrozole vs. letrozole alone
|
PFS 20.2 months vs. 10.2 months (HR 0.488; p = 0.0004)
PFS 26.1 months vs. 5.7 months (HR 0.299; p < 0.0001) in non-Cyclin D1 amplified
PFS 18.1 months vs. 11.1 months (HR 0.508; p = 0.0046) in Cyclin D1 amplified
|
PALOMA-2
Phase III
NCT01740427
[57]
|
HR+/HER2-
Postmenopausal
Advanced BC
No prior systemic treatment
|
Palbocilib + letrozole vs. placebo + letrozole
|
PFS 24.8 months vs. 14.5 months (HR 0.58; p < 0.001)
|
PALOMA-3
Phase III
NCT01942135
[58]
|
HR+/HER2-
MBC
Prior endocrine therapy
|
Palbociclib + fulvestrant
vs. placebo + fulvestrant
|
PFS 9.5 months vs. 4.6 months (HR 0.46; p < 0.0001)
|
Ribociclib
|
MONALEESA-2
Phase III
NCT01958021
[59]
|
HR+/HER2-
Postmenopausal
Advanced or MBC
|
Ribociclib + letrozole vs. placebo + letrozole
|
PFS 25.3 months vs. 16.0 months (HR 0.568; p < 0.0001)
|
MONALEESA-3
Phase III
NCT02422615
[60]
|
HR+/HER2-
Advanced BC
No prior treatment or prior endocrine therapy
|
Ribociclib + fulvestrant vs. placebo + fulvestrant
|
PFS 20.5 months vs. 12.8 months (HR 0.593; p < 0.001)
|
Abemaciclib
|
MONARCH-2
Phase III
NCT02107703
[61]
|
HR+/HER2-
Advanced or MBC
Prior endocrine treatment
|
Abemaciclib + fulvestrant vs. fulvestrant alone
|
PFS 16.4 months vs. 9.3 months (HR 0.553; p < 0.001)
|
MONARCH-3
Phase III
NCT02246621
[62]
|
HR+/HER2-
Advanced or MBC
Prior endocrine treatment
|
Abemaciclib + anastrozole or letrozole vs. placebo + anastrozole or letrozole
|
PFS 28.18 months vs. 14.76 months (HR 0.546; p < 0.0001)
|