TABLE 1.
Summary clinical RCT trials of PI3K/AKT/mTOR inhibitors in breast cancer.
| Drug | Target | Study | Phase | Patients population | Therapy line | Regimen | Outcome |
|---|---|---|---|---|---|---|---|
| Buparlisib (BKM120), oral | Class I PI3K- | BELLE-2 (NCT01610284) | III | Postmenopausal, HR(+)/HER2(−), AI-resistant locally advanced or mBC | Second-line or later | Buparlisib + fulvestrant | mPFS: 6.9 vs. 5.0 m (HR 0.78, p = 0.00021) |
| Placebo + fulvestrant | mPFS: 6.8 vs. 4.0 m (HR 0.76, p = 0.014) in PIK3CA-mutant subset | ||||||
| p110α | mOS: 33.2 vs. 30.4 m (HR 0.87, p = 0.045) | ||||||
| p110β | BELLE-3 (NCT01633060) | III | Postmenopausal, HR(+)/HER2(−), mTOR inhibitor-resistant, locally advanced or mBC | Second-line or later | Buparlisib + fulvestrant | mPFS: 3.9 vs. 1.8 m (HR 0.67, p = 0.0003) | |
| p110δ | Placebo + fulvestrant | ||||||
| p110γ | NeoPHOEBE (NCT01816594) | II | HER2(+) primary BC | Neoadjuvant | Buparlisib + trastuzumab + paclitaxel | ORR: 69 vs. 33% (p = 0.053) | |
| Placebo + trastuzumab + paclitaxel | pCR: 32 vs. 40% (p = 0.811) | ||||||
| BELLE-4 (NCT01572727) | II/III | HER2(−) primary with locally advanced or mBC | First-line | Buparlisib + paclitaxel | mPFS: 8.0 vs. 9.2 m (HR 1.18) | ||
| Placebo + paclitaxel | mPFS: 9.1 vs. 9.2 m (HR 1.17) in PIK3CA-mutant subset | ||||||
| Pictilisib (GDC-0941), oral | Class I PI3K- | PEGGY (NCT01740336) | II | HR(+)/HER2(−) locally advanced or mBC | Second-line or later | Pictilisib + paclitaxel | mPFS: 8.2 vs. 7.8 m (HR 0.95, p = 0.83) |
| p110α | Placebo + paclitaxel | mPFS: 7.3 vs. 5.8 m (HR 1.06, p = 0.88) in PIK3CA-mutant subset | |||||
| p110δ | FERGI (NCT01437566) | II | Postmenopausal, ER (+)/HER2(−), AI-resistant advanced or mBC | Second-line or later | Pictilisib + fulvestrant | mPFS: 6.6 vs. 5.1 m (HR 0.74, p = 0.096) | |
| Placebo + fulvestrant | mPFS: 6.5 vs. 5.1 m (HR 0.74, p = 0.268) in PIK3CA-mutant subset | ||||||
| Alpelisib (BYL719), oral | Class I PI3K- | SOLAR-1 (NCT02437318) | III | PIK3CA-mutated, previously received endocrine therapy, HR (+)/HER2(−) advanced BC | First or second-line | Alpelisib + fulvestrant | mPFS: 11.0 vs. 5.7 m (HR 0.65, p = 0.00065) in PIK3CA-mutant subset |
| p110α | Placebo + fulvestrant | ORR: 26.6 vs. 12.8% in PIK3CA-mutant subset | |||||
| p110α-H1047R | NEO-ORB (NCT01923168) | II | Postmenopausal, HR (+)/HER2(−) early stage BC | Neoadjuvant | Alpelisib + letrozole | ORR: 63 vs. 61% in PI3K wide-type subset | |
| p110α-E545K | Placebo + letrozole | ORR: 43 vs. 45% in PI3K-mutant subset | |||||
| Taselisib (GDC-0032), oral | Class I PI3K- | LORELEI (NCT02273973) | II | HR (+)/HER2(−) operable early stage BC | Neoadjuvant | Taselisib + letrozole | ORR: 50 vs. 39% (OR 1.55, p = 0.049) |
| p110δ | Placebo + letrozole | ORR: 56 vs. 38% (OR 2.03, p = 0.033) in PIK3CA-mutant subset | |||||
| p110α | SANDPIPER (NCT02340221) | III | HR(+)/HER2(−), AI resistant locally advanced or mBC | Second-line or later | Taselisib + fulvestrant | mPFS: 7.4 vs. 5.4 m (HR 0.70, p = 0.0037) | |
| p110γ | Placebo + fulvestrant | ||||||
| Capivasertib (AZD-5363), oral | Akt1 Akt2 Akt3 | FAKTION (NCT01992952) | II | HR(+)/HER2(−), AI-resistant advanced BC | Second-line or later | Capivasertib + fulvestrant | mPFS: 10.3 vs. 4.8 m (HR 0.58, p = 0.0035) |
| Placebo + fulvestrant | mOS: 26.0 vs. 20.0 m (HR 0.59, p = 0.071) | ||||||
| Ipatasertib (GDC-0068), oral | Akt1 Akt2 Akt3 | LOTUS (NCT02162719) | II | Primary locally advanced or mTNBC | First-line | Ipatasertib + paclitaxel | mPFS: 6.2 vs. 4.9 m (HR 0.60, p = 0.037) |
| Placebo + paclitaxel | mPFS: 6.2 vs. 3.7 m (HR 0.59, p = 0.18) in PTEN-low cohort | ||||||
| Everolimus, oral | mTOR1 | BOLERO-2 (NCT00863655) | III | HR (+)/HER2(−), AI-resistant and postmenopausal advanced BC | Second-line or later | Everolimus + exemestrane | mPFS: 10.6 vs. 4.1 m (HR 0.36, p < 0.001) |
| Placebo + exemestrane | ORR: 7 vs. 0.4% (p < 0.001) | ||||||
| MANTA (NCT02216786) | II | HR (+), postmenopausal and AI-resistant locally advanced or mBC | Second-line or later | Everolimus + fulvestrant | mPFS: 12.3 vs. 5.4 m (HR 0.63, p = 0.01) | ||
| Fulvestrant | |||||||
| PrE0102 (NCT01797120) | II | HR (+)/HER2(−), AI-resistant and postmenopausal mBC | Second-line or later | Everolimus + fulvestrant | mPFS: 10.3 vs. 5.1 m (HR 0.61, p = 0.02) | ||
| Placebo + fulvestrant | ORR: 18.2 vs. 12.3% (p = 0.47) | ||||||
| BOLERO-1 (NCT00876395) | III | HER2(+), primary advanced BC | First-line | Everolimus + trastuzumab | mPFS: 14.9 vs. 14.5 m (HR 0.89, p = 0.12) | ||
| Placebo + trastuzumab | mPFS: 20.3 vs. 13.1 m (HR 0.66, p = 0.0049) in HR (-) tumors | ||||||
| BOLERO-3 (NCT01007942) | III | HER2(+), taxane-pretreated and trastuzumab-resistant advanced BC | Second-line or later | Everolimus + trastuzumab + vinorelbine | mPFS: 7.0 vs. 5.8 m (HR 0.78, p = 0.0067) | ||
| Placebo + trastuzumab+ vinorelbine | |||||||
| Temsirolimus (CCI-779), intravenous | mTOR | HORIZON (NCT00083993) | III | HR(+), postmenopausal, AI-naïve advanced BC | First-line | Temsirolimus + letrozole | mPFS: 8.9 vs. 9.0 m (HR 0.90, p = 0.25) |
| Placebo + letrozole | mPFS: 9.0 vs. 5.6 m (HR 0.70, p = 0.009) in age ≤ 65 years subgroup |
AI, aromatase inhibitor; mBC, metastatic breast cancer.