Table Info

Table 1.

Published clinical trials combining ET and inhibitors of the PI3K/Akt/mTOR pathway

Name of trial	Study design	Comparators	Primary endpoint
mTOR inhibitors plus ET
BOLERO-2 [86]	Phase III RCT 2 arms 724 patients	Everolimus/exemestane vs. placebo/exemestane	PFS 7.8 vs. 3.2 months HR 0.45; 95% CI: 0.38–0.54; P < 0.0001
BOLERO-6 [87]	Phase II RCT 3 arms 309 patients	Everolimus/exemestane vs. everolimus alone vs. capecitabine alone	PFS 8.4 vs. 6.8 vs. 9.6 months Everolimus/exemestane vs. everolimus: HR 0.74 (90% CI: 0.57–0.97) Everolimus/exemestane vs. capecitabine: HR 1.26 (90% CI: 0.96–1.66)
HORIZON [88]	Phase III RCT 2 arms 1,112 patients	Letrozole/temsirolimus vs. letrozole/placebo	PFS 8.9 vs. 9.0 months HR 0.90; 95% CI: 0.76–1.07; P = 0.25
TAMRAD [89]	Phase II open-label 2 arms 111 patients	Tamoxifen/everolimus vs. tamoxifen alone	6-month CBR 61% (95% CI: 47–74) vs. 42% (95% CI: 29–56); P = 0.045
PrE0102 [90]	Phase II RCT 2 arms 131 patients	Fulvestrant/everolimus vs. fulvestrant/placebo	PFS 10.3 vs. 5.1 months HR 0.61; 95% CI: 0.40–0.92; P = 0.02
NCT02049957 [91]	Phase Ib/II open-label 2 cohorts 118 patients	Everolimus-sensitive group sapanisertib/exemestane or fulvestrant vs. everolimus-resistant group sapanisertib/exemestane or fulvestrant	16-week CBR 45% (95% CI: 31.1–59.7) vs. 23% (95% CI: 11.8–38.6)
MANTA [92]	Phase II open-label 3 arms 333 patients	Fulvestrant/vistusertib (continuous or intermittent dosing) vs. fulvestrant/everolimus vs. fulvestrant alone	PFS 7.6 (daily vistusertib) and 8.0 (intermittent vistusertib) vs. 12.3 vs. 5.4 months Fulvestrant/daily vistusertib vs. fulvestrant: HR 0.88; 95% CI: 0.63–1.24; P = 0.46 Fulvestrant/intermittent vistusertib vs. fulvestrant: HR 0.79; 95% CI: 0.55–1.12; P = 0.16 Fulvestrant/daily vistusertib vs. fulvestrant/everolimus: HR 0.63; 95% CI: 0.45–0.90; P = 0.01 Fulvestrant/intermittent vistusertib vs. fulvestrant/everolimus: HR 0.71; 95% CI: 0.49–1.01; P = 0.06
TRINITI-1 [93]	Phase I/II open-label single-arm 95 patients	Ribociclib/everolimus/exemestane	CBR at week 24; 41.1% (95% CI: 31.1–51.6)
NCT02123823 [94]	Phase Ib/II open-label 2 arms 140 patients	Xentuzumab/everolimus/exemestane vs. everolimus/exemestane	PFS 7.3 vs. 5.6 months HR 0.97; 95% CI 0.57–1.65; P = 0.9057
PI3K inhibitors plus ET
BELLE-2 [95]	Phase III RCT 2 arms 1,147 patients	Buparlisib/fulvestrant vs. placebo/fulvestrant	PFS total population 6.9 vs. 5.0 months HR 0.78; 95% CI: 0.67–0.89; P = 0.00021 PFS PI3K pathway-activated patients 6.8 vs. 4.0 months HR 0.76; 95% CI: 0.60–0.97; P = 0.014
BELLE-3 [96]	Phase III RCT 2 arms 432 patients	Buparlisib/fulvestrant vs. placebo/fulvestrant	PFS 3.9 vs. 1.8 months HR 0.67; 95% CI: 0.53–0.84; P = 0.00030
SOLAR-1 [97]	Phase III RCT 2 arms 572 patients	Alpelisib/fulvestrant vs. placebo/fulvestrant	PFS 11.0 vs. 5.7 months HR 0.65; 95% CI: 0.50–0.85; P < 0.001 in PIK3CA-mutant patients
NCT01870505 [98]	Phase I dose-escalation 2 arms 14 patients	Arm A: alpelisib/letrozole Arm B: alpelisib/exemestane	DLTs were maculopapular rash, hyperglycemia, and abdominal pain 8-week best response SD in 5 patients and PR in 1 patient
NCT01791478 [99]	Phase Ib Single-arm 26 patients	Letrozole/alpelisib	MTD of alpelisib plus letrozole at 300 mg/day CBR 35%; 95% CI: 17–56% (44% for PIK3CA-mutant vs. 20% for PIK3CA wild-type patients)
NCT01219699 [100]	Phase Ib open-label Single-arm 87 patients	Alpelisib/fulvestrant	MTD of alpelisib combined with fulvestrant 400 mg once daily, and the RP2D 300 mg PFS at the MTD 5.4 months (95% CI: 4.6–9.0)
FERGI [101]	Phase II RCT 2 arms, part 1 and 2 (only patients with PIK3CA mutations) 229 patients	Pictilisib/fulvestrant vs. placebo/fulvestrant	Part 1 PFS 6.6 vs. 5.1 months HR 0.74; 95% CI: 0.52–1.06; P = 0.096 Part 2 PFS 5.4 vs. 10.0 months HR 1.07; 95% CI: 0.53–2.18; P = 0.84
NCT01082068 [102]	Phase I/II open-label 2 arms 21 patients in phase I and 51 patients in phase II	Arm A: pilaralisib/letrozole Arm B: voxtalisib/letrozole	Arm A: ORR 4% (90% CI: 0.2–18.3) PFS 8 weeks (90% CI: 7.7–16.1) Arm B: no patient achieved ORR PFS 7.9 weeks (90% CI: 7.1–15.7)
BYlieve [103]	Phase II open-label 3 cohorts 127 patients	Alpelisib/fulvestrant	50.4% (95% CI: 41.2–59.6) alive without disease progression at 6 months
NCT02077933 [104]	Phase Ib open-label Breast cancer expansion cohort 11 patients	Alpelisib/exemestane with or without everolimus	Triplet escalation phase: MTD was alpelisib 200 mg, everolimus 2.5 mg, exemestane 25 mg Triplet cohort: ORR of 25.0% and DCR of 62.5% (90% CI: 28.9–88.9)
NCT02058381 [105]	Phase Ib open-label 2 arms 29 patients	Arm A: tamoxifen/goserelin/alpelisib Arm B: tamoxifen/goserelin/buparlisib	Arm A: treatment discontinuation 18.8%, PFS 25.2 months (95% CI: 2.7–36.3) Arm B: treatment discontinuation 53.8%, PFS 20.6 months (95% CI: 2.9 to not reached)
NEO-ORB [106]	Phase II RCT 2 arms 257 patients	Letrozole/alpelisib vs. letrozole/placebo	ORR 43% vs. 45% for PIK3CA-mutant patients and 63 vs. 61% for PIK3CA wild-type patients pCR 1.7% vs. 3% for PIK3CA-mutant patients and 2.8% vs. 1.7% for PIK3CA wild-type patients
NCT02734615 [107]	Phase I open-label, dose-escalation 3 arms 198 patients	Arm A: LSZ102 alone Arm B: LSZ102/ribociclib Arm C: LSZ102/alpelisib	Arm A: DLTs 5%, ORR 1.3% (95% CI: 0.0–7.0) Arm B: DLTs 3%, ORR 16.9% (95% CI: 9.3–27.1%) Arm C: DLTs 19%, ORR 7% (95% CI: 1.5–19.1)
SANDPIPER [108]	Phase III RCT 2 arms 516 patients	Taselisib/fulvestrant vs. placebo/fulvestrant	PFS 7.4 vs. 5.4 months HR 0.70; 95% CI: 0.56–0.89; P = 0.0037
NCT01296555 [109]	Phase II open-label single arm 60 patients	Taselisib/fulvestrant	CBR total population 29.5% (95% CI: 16.8–45.2) CBR PIK3CA-mutant 38.5% (95% CI: 13.9–68.4) ORR total population 22.7% (95% CI: 11.5–37.8) ORR PIK3CA-mutant 38.5% (95% CI: 13.9–68.4)
LORELEI [110]	Phase II RCT 2 arms 334 patients	Taselisib/letrozole vs. placebo/letrozole	ORR 38% for placebo vs. 50% for taselisib OR 1.55; 95% CI: 1.00–2.38; P = 0.049 pCR 2% for taselisib vs. 1% for placebo OR 3.07; 95% CI: 0.32–29.85; P = 0.37
PIPA [111]	Phase Ib expansion Single-arm 25 patients	Palbociclib/taselisib/fulvestrant	ORR 37.5% (95% CI: 18.8–59.4) CBR 58.3% (95% CI: 36.6–77.9) PFS 7.2 months (95% CI: 3.9–9.9)
NCT03006172 [112]	Phase I open-label, dose-escalation 2 arms 70 patients	Arm A: galone (GDC-0077)/letrozole Arm B: galone (GDC-0077)/palbociclib/letrozole	Arm A: no DLTs, confirmed PR 8%, CBR 35% Arm B: no DLTs, confirmed PR 36%, CBR 76%
Akt inhibitors plus ET
FAKTION [113]	Phase II RCT 2 arms 140 patients	Capivasertib/fulvestrant vs. placebo/fulvestrant	PFS 10.3 vs. 4.8 months HR 0.58; 95% CI: 0.39–0.84; P = 0.0044
NCT01776008 [71]	Phase II open-label single-arm 16 patients	MK-2206/anastrozole plus goserelin for premenopausal patients	pCR rate 0% (90% CI: 0–17.1)
TAKTIC [114]	Phase Ib open-label 3 arms 25 patients	Arm A: ipatasertib/AI Arm B: ipatasertib/fulvestrant Arm C: ipatasertib/fulvestrant/palbociclib	Arm C (12 patients): no DLTs/discontinuations PR 2/12 patients SD 3/12 patients
Dual PI3K/mTOR inhibitors plus ET
NCT02684032 [115]	Phase Ib dose-escalation/expansion 3 arms 35 patients	Arm A: gedatolisib/palbociclib/letrozole first-line Arm B: gedatolisib/palbociclib/fulvestrant second-line, CDKi 4/6 naive Arm C: gedatolisib/palbociclib/fulvestrant prior CDKi 4/6	Gedatolisib/palbociclib/letrozole DLTs 4/15 patients, SD/PR 53%/33% Gedatolisib/palbociclib/fulvestrant DLTs 4/20 patients, SD/PR 55%/20%

RCT: randomized controlled trial; PFS: progression-free survival; HR: hazard ratio; CBR: clinical benefit rate; DLT: dose-limiting toxicity; SD: stable disease; PR: partial response; MTD: maximum tolerated dose; ORR: objective response rate; pCR: pathologic complete response; CDKi: CDK inhibitor; DCR: disease control rate; RP2D: recommended phase 2 dose

Declarations

Author contributions

SL designed, identified key literature, and edited the review. AS, JDC, and ML contributed to the literature search, designed the figures and table. All authors wrote sections of the manuscript, contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

JDC is funded by the National Institute for Health Research Academic Clinical Fellowship Award (ACF-2020-13-009) and the Oxford Hospital’s Charity (1415). SL is funded by Against Breast Cancer. The funders had no role in design, data collection and analysis, preparation of the manuscript, or decision to publish.

Copyright

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