Table 1 Main clinical trials with targeted agents for ER+/HER2- advanced/metastatic breast cancer: mTOR inhibitors, PI3K inhibitors, and Akt inhibitors

mTOR

mTOR inhibitor

Evelorimus

BOLERO-2 [17–19]

III

nsAI failure

EXE + evelorimus vs. EXE

10.6 mo vs. 4.1 mo

n.s.

BOLERO-4 NCT01698918

II

First line

LET + evelorimus vs. LET

BOLERO-6 NCT01783444

II

nsAI failure

EXE + evelorimus vs. EXE vs. capecitabine

TAMRAD [20]

II

First line

TAM + evelorimus vs. TAM

61 % vs. 42 %

8.5mo vs. 4.5mo

Not reached vs. 32.9mo

Tensirolimus

HORIZON [21]

III

First line

LET + tensirolimus vs. LET

n.s.

mTORC

mTORC dual TORC1/2 inhibitor

MLN0128

NCT02049957

I/II

MLN0128 + EXE vs. MLN0128 + FUL

PI3K

Pan-PI3 K inhibitor

BKM120

BELLE-2 NCT01610284

III

AI failure

Fulvestrant + BKM120 vs. fulvestrant

BELLE-3 NCT01633060

III

mTOR inhibitor resisetance

Fulvestrant + BKM120 vs. fulvestrant

BELLE-4 NCT01572727

III

First line

BKM120 vs. BKM120 + PTX

n.s.

PI3K-α inhibitor

BYL719

NCT02058381

II

Premenopausal patients

BYL719 + TAM + Gos vs. BKM120 + TAM + Gos vs. TAM + Gos

Pan-PI3K inhibitor/dual PI3K/mTOR inhibitor

XL147/XL765

NCT01082068

I/II

nsAI failure

XL147 + LET vs. XL765 + LET

dual PI3K/mTOR inhibitor

GDC0941/GDC0980

NCT01437566

II

AI failure

Fulvestrant + GDC0941 vs. fulvestrant + GDC0980 vs. fulvestrant

ORR 7.9 % vs. unknown vs. 6.3 %

6.6mo vs. unknown vs. 5.1mo

Akt

Akt inhibitor

AZD2014

MANTA NCT02216786

II

AI failure

AZD2014 + FUL vs. everolimus + FUL vs. FUL

AZD5363

BEECH NCT01625286

I/II

Part B: PI3CA mut

AZD5363 + wPTX vs. wPTX

MK2206

NCT01277757

II

PIK3CA mut AKT mut PTEN loss/mut

Monotherapy