. Author manuscript; available in PMC: 2021 Nov 1.

Published in final edited form as: Drugs. 2020 Nov;80(16):1685–1697. doi: 10.1007/s40265-020-01394-w

Table 2:

Summary of Key Clinical Trials assessing PI3K/AKT/mTOR Pathway Inhibitors in HR+ Breast Cancer

Trial Name	NCT Identifier	Phase	Population	Treatment	Treatment Line	Outcome
Mtorc1 Inhibitors
BOLERO-2²⁹	00863655	III	ER+/HER2−mBC after AI n=724	Exemestane ± everolimus	Subsequent line after progression on AI	Median PFS was 6.9 mos for everolimus plus exemestane vs 2.8 mos for placebo + exemestane (HR for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001)
TAMRAD³⁰	01298713	II	ER+/HER2−mBC after AI n= 111	Tamoxifen ± everolimus	Subsequent line after progression on AI	Primary end point was clinical benefit rate (CBR). 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased to 8.6 mos with tamoxifen + everolimus from 4.5 mos with tamoxifen alone
PrE0102³¹	01797120	II	HR+/HER2−mBC after AI n= 131	Fulvestrant ± everolimus	Subsequent line After progression on AI	Median PFS was 10.3 mos with everolimus + fulvestrant vs 5.1 mos for fulvestrant + placebo (HR 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02)
e3 (S1207)⁸⁴	01674140	III	HR+/HER2− high risk, localized BC	Standard adjuvant ET ± one year of everolimus	Adjuvant treatment to prevent disease recurrence	Primary objectives are to assess whether addition of everolimus × 1 year to standard adjuvant ET improves overall survival (OS) and distant recurrence-free survival (DRFS) in this patient population.
Pan-PI3K Inhibitors
BELLE-2³⁸	01610284	III	ER+/HER2−locally advanced BC or mBC n= 1147	Fulvestrant ± buparlisib	Subsequent line after progression on AI	Median PFS was 6.9 mos with buparlisib vs 5.0 mos in placebo group (p<0.001); PIK3CA-mut increase in PFS for buparlisib compared to placebo (7 vs 3.2 mos, HR 0.56, p<0.001)
BELLE-3³⁹	01633060	III	ER+/HER2−locally advanced BC or mBC n= 432	Fulvestrant ± buparlisib	Subsequent line for progression/relapse after ET + everolimus	Median PFS was 3.9 mos with buparlisib vs 1.8 mos with placebo (HR 0.67, 95% Cl 0.53–0.84, one-sided p=000030); high rates of grade 3–4 adverse events
Pan-AKT Inhibitors
FAKTION⁴⁴	01992952	II	ER+/HER2−locally advanced or mBC n= 140	Fulvestrant ± capivasertib	Subsequent line for progression/relapse after AI	Median PFS was 10.3 mos (95% CI.5·0–13·2) with capivasertib vs 4.8 mos (3.1–7.7) with placebo [HR 0.58 (95% CI 0.39–0.84); two-sided p=0.0044, one-sided log rank test p=0.0018]
NCT01226316⁴⁶	01226316	I	AKT1^E17K-mutant ER⁺ MBC n=63	Capivasertib or capivasertib + fulvestrant	Subsequent line for progression on prior therapy	ORR was 20% with capivasertib monotherapy, 36% with fulvestrant + capivasertib in fulvestrant-pretreated patients, 20% with combination in fulvestrant-naive patients
Isoform-specific PI3K Inhibitors
SOLAR-1⁵⁵	02437318	III	HR+/HER2−mBC n =572	Fulvestrant ± alpelisib	Subsequent line for progression/relapse after ET	Patients with PIK3CA-mut PFS was 11.0 mos (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group vs 5.7 mos (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001)
NEO-ORB⁶²	01923168	II	HR+/HER2−localized BC n= 257	Letrozole ± alpelisib	Neoadjuvant therapy	ORR was similar for the alpelisib + letrozole vs. placebo plus letrozole (PIK3CA-mutant, 43% vs. 45%, p= 0.435; PIK3CA-wild-type, 63% vs. 61%, p= 0.611). Low pCR rates in all groups.
SANDPIPER⁶⁷	02340221	III	PIK3CA-mut HR+/HER2−locally advanced BC or mBC n= 516	Fulvestrant ± taselisib	Subsequent line for progression/relapse after AI	Median PFS was 7.4 mos in taselisib + fulvestrant vs 5.4 mos in fulvestrant alone (HR 0.70, p= 0.0037)
LORELEI⁶⁸	02273973	II	ER+/HER2−localized breast cancer n= 334	Letrozole ± taselisib	Neoadjuvant therapy	OR was 39% in the placebo group vs 50% in the taselisib group (OR 1.55, 95% CI 1.00–2.38; p=0.049) and in PIK3CA-mut subset 38% vs 56% (OR 2.03, 95% CI 1.06–3.88; p=0.033). No significant differences in pCR between the two groups.
BYLIEVE⁶⁴	03056755	II	PIK3CA-mut HR+/HER2−mBC n= 127 (cohort A)	ET ± alpelisib	Subsequent line for progression/relapse after CKDi	Trial ongoing; Preliminary results of the cohort of patients treated with CDKi + AI immediately prior met primary end point at median follow-up was 11.7 mos: proportion of pts without disease progression at 6 mos was 50.4% (95% CI, 41.2–59.6)