Table 3.
Clinical trials of AKT and mTOR inhibitors in ER+/HER2− breast cancer.
| Target | Drug | Study (Phase) | Patient Population | Regimen and Outcome | FDA/EMA Approved | Reference |
|---|---|---|---|---|---|---|
| AKT1-3 | Capivasertib (AZD5363) | BEECH (II) |
ER (+), HER2 (−) ABC/MBC (first-line) | capivasertib + paclitaxel vs. placebo + paclitaxel (mPFS: 10.9 vs. 8.4 months; HR: 0.80; p = 0.308) PIK3CA+ sub-population (mPFS: 10.9 vs. 10.8 months; HR: 1.11; p = 0.760) |
N | [101] |
| FAKTION (II) |
ER (+)/HER (−) ABC/MBC; Postmenopausal relapsed or progressed on AI |
capivasertib + fulvestrant vs. placebo + fulvestrant (mPFS: 10.3 vs. 4.8 months; HR: 0.58; p = 0.0044; mOS: 29.3 vs. 23.4 months; HR: 0.66; p = 0.035) |
[102,103] | |||
| Pan-AKT | MK-2206 |
NCT01776008 (II) |
Endocrine resistant, ER+ breast cancer | 0% pCR | N | - |
| mTOR (mTORC1) |
Everolimus (RAD001) | BOLERO-2 (III) |
ER (+)/HER2−, AI-resistant and postmenopausal ABC |
Everolimus + exemestrane vs. placebo + exemestrane (final PFS:11.0 vs. 4.1 months; HR: 0.38; p < 0.0001) | [104] | |
| MANTA (II) |
HR+, postmenopausal and AI-resistant locally ABC or MBC | Everolimus +fulvestrant vs. fulvestrant (mPFS: 12.3 vs. 5.4 months; HR: 0.63; p = 0.01) | A | [105] | ||
| PrE0102 (II) |
ER (+)/HER2−, AI-resistant and postmenopausal MBC | Everolimus + fulvestrant vs. placebo + fulvestrant (mPFS:10.3 vs.5.1 months; HR: 0.61; p = 0.02) ORR: 18.2 vs. 12.3%; p = 0.47 |
[106] | |||
| BOLERO-6 (III) |
ER (+)/HER2−ABC | Everolimus + exemestrane vs. Exemestrane vs. capecitabine mOS: 23.1 vs. 29.3 months vs. 25.6 months | [107] | |||
|
NCT02123823 (I-II) |
ER (+)/HER2− ABC and MBC |
xentuzumab + everolimus + exemestane, vs. exemestane + everolimus (mPFS: 7.3 vs. 5.6 months; p = 0.9057) | [108] | |||
| mTOR (mTORC1/2) |
MLN0128 |
NCT02049957 (I-II) |
HR+/HER2− and AI-resistant MBC |
everolimus-sensitive vs. everolimus-resistant cohorts, 1 CBR-16: 45% vs. 23%, 2 ORR: 8% vs. 2% |
N | [109] |
| Apanisertib |
NCT02756364 (II) |
HR+/HER2− and AI-resistant MBC |
NA | N | - | |
| Pan-mTOR | Temsirolimus | HORIZON (III) |
HR+, postmenopausal and AI-naïve ABC | Temsirolimus vs. placebo + letrozole (mPFS: 9.0 vs. 5.6 months; HR: 0.7, p < 0.009) |
N | [110] |
1 CBR-16, clinical benefit rate at 16 weeks; 2 ORR, overall response rate.