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 RCT2 arms724 patients | Everolimus/exemestane vs. placebo/exemestane | PFS 7.8 vs. 3.2 monthsHR 0.45; 95% CI: 0.38–0.54; P < 0.0001 |
| BOLERO-6 [87] | Phase II RCT3 arms309 patients | Everolimus/exemestane vs. everolimus alone vs. capecitabine alone | PFS 8.4 vs. 6.8 vs. 9.6 monthsEverolimus/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 RCT2 arms1,112 patients | Letrozole/temsirolimus vs. letrozole/placebo | PFS 8.9 vs. 9.0 monthsHR 0.90; 95% CI: 0.76–1.07; P = 0.25 |
| TAMRAD [89] | Phase II open-label2 arms111 patients | Tamoxifen/everolimus vs. tamoxifen alone | 6-month CBR61% (95% CI: 47–74) vs. 42% (95% CI: 29–56); P = 0.045 |
| PrE0102 [90] | Phase II RCT2 arms131 patients | Fulvestrant/everolimus vs. fulvestrant/placebo | PFS 10.3 vs. 5.1 monthsHR 0.61; 95% CI: 0.40–0.92; P = 0.02 |
| NCT02049957 [91] | Phase Ib/II open-label2 cohorts118 patients | Everolimus-sensitive group sapanisertib/exemestane or fulvestrant vs. everolimus-resistant group sapanisertib/exemestane or fulvestrant | 16-week CBR45% (95% CI: 31.1–59.7) vs. 23% (95% CI: 11.8–38.6) |
| MANTA [92] | Phase II open-label3 arms333 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 monthsFulvestrant/daily vistusertib vs. fulvestrant: HR 0.88; 95% CI: 0.63–1.24; P = 0.46Fulvestrant/intermittent vistusertib vs. fulvestrant: HR 0.79; 95% CI: 0.55–1.12; P = 0.16Fulvestrant/daily vistusertib vs. fulvestrant/everolimus: HR 0.63; 95% CI: 0.45–0.90; P = 0.01Fulvestrant/intermittent vistusertib vs. fulvestrant/everolimus: HR 0.71; 95% CI: 0.49–1.01; P = 0.06 |
| TRINITI-1 [93] | Phase I/II open-labelsingle-arm95 patients | Ribociclib/everolimus/exemestane | CBR at week 24; 41.1% (95% CI: 31.1–51.6) |
| NCT02123823 [94] | Phase Ib/II open-label2 arms140 patients | Xentuzumab/everolimus/exemestane vs. everolimus/exemestane | PFS 7.3 vs. 5.6 monthsHR 0.97; 95% CI 0.57–1.65; P = 0.9057 |
| PI3K inhibitors plus ET | |||
| BELLE-2 [95] | Phase III RCT2 arms1,147 patients | Buparlisib/fulvestrant vs. placebo/fulvestrant | PFS total population 6.9 vs. 5.0 monthsHR 0.78; 95% CI: 0.67–0.89; P = 0.00021PFS PI3K pathway-activated patients 6.8 vs. 4.0 monthsHR 0.76; 95% CI: 0.60–0.97; P = 0.014 |
| BELLE-3 [96] | Phase III RCT2 arms432 patients | Buparlisib/fulvestrant vs. placebo/fulvestrant | PFS 3.9 vs. 1.8 monthsHR 0.67; 95% CI: 0.53–0.84; P = 0.00030 |
| SOLAR-1 [97] | Phase III RCT2 arms572 patients | Alpelisib/fulvestrant vs. placebo/fulvestrant | PFS 11.0 vs. 5.7 monthsHR 0.65; 95% CI: 0.50–0.85; P < 0.001 in PIK3CA-mutant patients |
| NCT01870505 [98] | Phase I dose-escalation2 arms14 patients | Arm A: alpelisib/letrozoleArm B: alpelisib/exemestane | DLTs were maculopapular rash, hyperglycemia, and abdominal pain8-week best response SD in 5 patients and PR in 1 patient |
| NCT01791478 [99] | Phase IbSingle-arm26 patients | Letrozole/alpelisib | MTD of alpelisib plus letrozole at 300 mg/dayCBR 35%; 95% CI: 17–56% (44% for PIK3CA-mutant vs. 20% for PIK3CA wild-type patients) |
| NCT01219699 [100] | Phase Ib open-labelSingle-arm87 patients | Alpelisib/fulvestrant | MTD of alpelisib combined with fulvestrant 400 mg once daily, and the RP2D 300 mgPFS at the MTD 5.4 months (95% CI: 4.6–9.0) |
| FERGI [101] | Phase II RCT2 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 monthsHR 0.74; 95% CI: 0.52–1.06; P = 0.096Part 2 PFS 5.4 vs. 10.0 monthsHR 1.07; 95% CI: 0.53–2.18; P = 0.84 |
| NCT01082068 [102] | Phase I/II open-label2 arms21 patients in phase I and 51 patients in phase II | Arm A: pilaralisib/letrozoleArm 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 ORRPFS 7.9 weeks (90% CI: 7.1–15.7) |
| BYlieve [103] | Phase II open-label3 cohorts127 patients | Alpelisib/fulvestrant | 50.4% (95% CI: 41.2–59.6) alive without disease progression at 6 months |
| NCT02077933 [104] | Phase Ib open-labelBreast cancer expansion cohort11 patients | Alpelisib/exemestane with or without everolimus | Triplet escalation phase: MTD was alpelisib 200 mg, everolimus 2.5 mg, exemestane 25 mgTriplet cohort: ORR of 25.0% and DCR of 62.5% (90% CI: 28.9–88.9) |
| NCT02058381 [105] | Phase Ib open-label2 arms29 patients | Arm A: tamoxifen/goserelin/alpelisibArm 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 RCT2 arms257 patients | Letrozole/alpelisib vs. letrozole/placebo | ORR 43% vs. 45% for PIK3CA-mutant patients and 63 vs. 61% for PIK3CA wild-type patientspCR 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-escalation3 arms198 patients | Arm A: LSZ102 aloneArm B: LSZ102/ribociclibArm 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 RCT2 arms516 patients | Taselisib/fulvestrant vs. placebo/fulvestrant | PFS 7.4 vs. 5.4 monthsHR 0.70; 95% CI: 0.56–0.89; P = 0.0037 |
| NCT01296555 [109] | Phase II open-label single arm60 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 RCT2 arms334 patients | Taselisib/letrozole vs. placebo/letrozole | ORR 38% for placebo vs. 50% for taselisibOR 1.55; 95% CI: 1.00–2.38; P = 0.049pCR 2% for taselisib vs. 1% for placeboOR 3.07; 95% CI: 0.32–29.85; P = 0.37 |
| PIPA [111] | Phase Ib expansionSingle-arm25 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-escalation2 arms70 patients | Arm A: galone (GDC-0077)/letrozoleArm 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 RCT2 arms140 patients | Capivasertib/fulvestrant vs. placebo/fulvestrant | PFS 10.3 vs. 4.8 monthsHR 0.58; 95% CI: 0.39–0.84; P = 0.0044 |
| NCT01776008 [71] | Phase II open-labelsingle-arm16 patients | MK-2206/anastrozole plus goserelin for premenopausal patients | pCR rate 0% (90% CI: 0–17.1) |
| TAKTIC [114] | Phase Ib open-label3 arms25 patients | Arm A: ipatasertib/AIArm B: ipatasertib/fulvestrantArm C: ipatasertib/fulvestrant/palbociclib | Arm C (12 patients): no DLTs/discontinuationsPR 2/12 patientsSD 3/12 patients |
| Dual PI3K/mTOR inhibitors plus ET | |||
| NCT02684032 [115] | Phase Ib dose-escalation/expansion3 arms35 patients | Arm A: gedatolisib/palbociclib/letrozole first-lineArm B: gedatolisib/palbociclib/fulvestrant second-line, CDKi 4/6 naiveArm 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