Table 2.
Completed Clinical Trials of AKT Inhibitors in Breast Cancer
| AKT inhibitor | Trial name | Phase | Study arm | Study population (n. enrolled) | Study design | Primary endpoint | Efficacy outcome | Ref. |
|---|---|---|---|---|---|---|---|---|
| Capivasertib | STAKT | 0 (WoO) | Capivasertib or placebo | Early ER + BC (neoadjuvant) (n. 48) | Randomized, double-blind | Changes in AKT pathway markers | NA | [305] |
| D3610C00001 | I | Capivasertib monotherapy | PIK3CA-mut ER + mBC (part Cb) (n. 31) | Multipart, open label | Safety |
Tumor shrinkage: 46% ORR: 4% |
[306] | |
| D3610C00001 | I | Capivasertib +/- Fulvestrant | AKT1E17K mut ER + mBC (part D) (n. 63) | Multipart, open label | Safety |
ORR (monotherapy): 20% ORR (combination prior fulv.): 36% ORR (combination fulv. Naïve): 20% |
[307] | |
| FAKTION | Ib/II | Capivasertib or placebo + fulvestrant | ER + HER2- mBC, postmenopausal (n. 140) | Randomized, double-blind | PFS | mPFS: 10.3 (capiv) vs 4.8 (pbo) | [308] | |
| BEECH | Ib/II | Capivasertib or placebo + Paclitaxel | ER + HER2 – mBC (n. 110) | Randomized, double-blind | PFS in ITT and PIK3CA-mut pop |
mPFS ITT: 10.9 (capiv) vs. 8.4 (pbo) months mPFS PIK3CA-mut: 10.9 (capiv) vs 10.8 (pbo) months |
[309] | |
| PAKT | II | Capivasertib or placebo + paclitaxel | mTNBC (n. 140) | Randomized, double-blind | PFS | mPFS: 5.9 (capiv) vs. 4.2 (pbo) months | [310] | |
| Ipatasertib | FAIRLANE | II | Ipatasertib or placebo + paclitaxel | Early TNBC (neoadjuvant) (n. 151) | Randomized, double-blind | pCR in ITT and PTEN-low popul | pCR ITT: 17% (ipat) vs 13% (pbo) | [311] |
| pCR PTEN-low: 16% (ipat) vs. 13% (pbo) | ||||||||
| LOTUS | II | Ipatasertib or placebo + paclitaxel | mTNBC (n.124) | Randomized, double-blind | PFS in ITT and PTEN-low popul | mPFS ITT: 6.2 (ipat) vs 4.9 (pbo) months | [312] | |
| mPFS PTEN-low: 6.2 (ipat) vs. 3.7 (pbo) months NA | ||||||||
| MK-2206 | NA | 0 (WoO) | MK-2206 monotherapy | Early BC (neoadjuvant) (n. 12) | Open label, single arm | pAKT reduction in tumor tissue | NA | [313] |
| SU2C | Ib | MK-2206 + paclitaxel | mBC (expansion cohort) (n. 13) | Open label dose finding | MTD |
ORR: 23% CBR: 46% |
[314] | |
| NA | I | MK-2206 + anastrozole and/or fulvestrant | ER + HER2 – mBC (n. 31) | Open label dose finding | RP2D | CBR: 36.7% | [315] | |
| NA | I | MK-2206 + trastuzumab | HER2 + mBCa (n. 27) | Open label dose finding | MTD/RP2D |
ORR: 7.4% CBR: 22% |
[316] | |
| NA | I | MK-2206 +/- Lapatinib | HER2 + mBC (escalation + expansion cohort) (n. 8) | Open label dose finding | MTD/RP2D | ORR: 0% | [317] | |
| NA | Ib | MK-2206 + paclitaxel + trastuzumab | HER2 + mBC (n. 12) | Open label dose finding | RP2D | ORR: 75% | [318] | |
| NA | II | MK-2206 Monotherapy | PIK3CA/AKT mut or PTEN altered mBC (n. 27) | Open label single arm | ORR | ORR PIK3CA/AKT mut: 5.6% | [319] | |
| NA | II | MK-2206 + anastrozole | PIK3CA-mut ER + HER2 – early BC (n. 16) | Open label single arm | pCR |
ORR PTEN altered: 0% pCR rate: 0% |
[320] | |
| I-SPY2 | II | MK-2206 + standard NAT or standard NAT | Early BC (neoadjuvant) (n. 352) | Open label randomized adaptive | pCR |
pCR e-rate overall: 35% (exp) vs. 21% (contr) pCR e-rate (ER+/HER2-): 17% (exp) vs. 13% (contr)pCR e-rate (ER-/HER2+): 62% (exp) vs. 35% (contr) |
[321] |
Note: Adapted from [447]
Legend: AC doxorubicin and cyclophosphamide, BC breast cancer, Capiv capivasertib, CBR clinical benefit rate, Contr control arm, ER estrogen receptor, E-rate estimated-rate, Esp experimental arm, Fulv fulvestrant, HR hazard ratio, HT hormone therapy, Ipat ipatasertib, ITT intention-to-treat, m metastatic, mPFS median progression-free survival, MTD maximum tolerated dose, Mut mutated, NA not applicable, NAT neoadjuvant therapy, ORR objective response rate, Pbo placebo, pCR pathologic complete response, Popul population, RP2D recommended phase II dose, TNBC triple-negative breast cancer, WoO window of opportunity
aThese trials also enrolled patients with HER2+ advanced gastric cancer. However, only results about BC patients are reported