Table 1 Pivotal clinical trials comparing AI monotherapy with drug combinations including AIs and novel, targeted drugs
Study/phase | Patients | N | AI | Targeted drug | Efficacy/results |
|---|---|---|---|---|---|
I. Studies combining AIs with HER1/2 inhibitors | |||||
EORTC 30008 Phase III, randomised, double-blind, placebo-controlled trial | PMW with MBC HR-pos, HER2-pos or -neg HR-pos/HER2-pos (subgroup) No prior ET for MBC was allowed. | 1286 219 | Letrozole | Lapatinib | Median PFS in the ER-pos/HER2-pos subgroup: 8.2 months (combination LAP+ LET) vs 3.0 months for LET monotherapy, HR 0.71, 95% CI: 0.53–0.96 (P=0.019). |
TAnDEM study Phase III, randomised, open-label clinical trial | PMW with HR-pos/HER2-pos MBC TAM or ANA as ET for MBC allowed for up to 4 weeks before inclusion. | 207 | Anastrozole | Trastuzumab | Median PFS: 4.8 months (combination ANA+TZM) vs 2.4 months for ANA monotherapy, HR=0.63, 95% CI: 0.47–0.84 (P=0.0016). |
NCT00077025 Phase II, randomised placebo-controlled clinical trial | PMW with HR-pos MBC; No prior ET for MBC. | 94 | Anastrozole | Gefitinib | Median PFS: 14.7 months in combination group (ANA+GEF) vs 8.4 months in the ANA+PLAC subgroup; HR: 0.55, CI: 0.32–0.94; CBR ANA+GEF: 49% CBR ANA+PLAC: 34%. |
NCT00066378 Phase II randomised, double-blind, placebo-controlled trial | PMW with HR-pos MBC LABC in subgroup of patients; Prior ET for MBC allowed. | 71 | Anastrozole | Gefitinib | PFS rate at 1 year: 35% for ANA+GEF vs 32% for ANA+PLAC; ORR: 22% ANA+GEF vs 28% ANA+PLAC; median duration of response: 13.8 months in the ANA+GEF group vs 18.6 months in the ANA+PLAC. |
II. Studies combining AIs with mTOR inhibitors | |||||
HORIZON Phase III, randomised, double-blind, placebo-controlled trial | PMW with HR-pos LABC or MBC; at least one measurable lesions by RECIST; no prior AI therapy for either LABC or MBC; no adjuvant AI therapy during the last 12 months before inclusion. | 1112 | Letrozole | Temsirolimus | Overall PFS was similar in both arms: 8.9 vs 9 months; HR: 0.90, 95% CI: 0.76–1.07 (P=0.25); PFS in patients ⩽age 65 years (exploratory analysis): 9.0 months in LET+TEM group vs 5.6 months in LET monotherapy arm; HR 0.75, 95% CI: 0.60–0.93 (P=0.009); |
BOLERO-2 Phase III, randomised, double-blind, placebo-controlled trial | PMW with ER-pos/HER2-neg MBC refractory to previous LET or ANA monotherapy (recurrence during or within 12 months after the end of adjuvant therapy or within 1 month after the end of treatment for advanced disease. | 724 | Exemestane | Everolimus | Median PFS was 6.9 months with EXE+EVE and 2.8 months for EXE monotherapy; HR 0.43, CI 0.35–0.54 (P<0.001); Median central PFS: 10.6 (EXE+EVE) vs 4.1 months (EXE monotherapy); HR 0.36, 95% CI: 0.27–0.47 (P<0.001). |
III. Studies combining AIs with PI3K inhibitors | |||||
NCT01248494 Phase Ib, open-label clinical trial | PMW with ER-pos/HER2-neg MBC refractory to at least one line of ET in the MBC setting or diagnosed with MBC during or within 1 year of adjuvant ET. | 51 | Letrozole | Buparlisib | Clinical benefit rate at MTD of buparlisib: 31% 27% grade 3 adverse events. No grade 4 adverse events; Clinical efficacy not dependent on PIK3CA mutation status. |
IV. Studies combining AIs with CDK4/6 inhibitors | |||||
PALOMA-1/TRIO-18 Phase II, open-label, randomised trial | PMW with advanced ER-pos/HER2-neg BC without prior treatment for advanced disease; Cohort 1: inclusion based on HR/HER2-status; Cohort 2: as cohort 1 but in addition confirmed amplification of cyclin D1, loss of p16 or both. | 165 | Letrozole | Palbociclib | Median PFS: 20.2 (LET+PAL) vs 10.2 months (LET monotherapy); HR 0.488, 95% CI: 0.319–0.748 (P=0.0004); Cohort 1: median PFS: 5.7 months (LET) vs 26.1 months for the LET+PAL combination; HR 0.299, 95% CI: 0.156–0.572 (one-sided P>0.0001); Cohort 2: median PFS: 11.1 months for LET monotherapy vs 18.1 months for the LET+PAL combination, HR 0.508, 95% CI: 0.303–0.853 (one-sided P=0.0046) |
NCT01958021 Phase III, randomised, double-blind, placebo-controlled clinical trial | PMW with HR-pos/HER2-neg recurrent or MBC without prior therapy for advanced breast cancer. | 668 | Letrozole | Ribociclib | PFS rate at 18 months: 63% for the LET+RIB combination vs 42.2% for the LET monotherapy arm, Overall response rate (patients with measureable disease at baseline): 52.7% for the LET+RIB combination vs 37.1% for the LET monotherapy group (P<0.001). |
V. Studies combining AIs with fulvestrant | |||||
FACT-trial Phase III, open-label, randomised, clinical trial | PMW or PREMPW receiving a GnRH agonist, with HR-pos MBC and relapse after or during primary treatment. | 514 | Anastrozole | Fulvestrant | Median TTP was 10.8 months for the ANA+FULV combination vs 10.2 months in the ANA monotherapy arm, HR 0.99, 95% CI: 0.81–1.20 (P=0.91); median overall survival was OS: 37.8 months and 38.2 months, respectively (P=1.00); |
SoFEA Phase III, randomised, placebo-controlled clinical trial | PMW with HR-pos relapse or advanced BC (MBC or LABC) during therapy with an NSAI (NSAI given for at least 12 months as adjuvant therapy or at least 6 months for MBC). | 723 | Anastrozole Exemestane | Fulvestrant | PFS: ANA+FULV: 4.4 months (CI: 3.4–5.4 mo); FULV+PLAC: 4.8 months (CI: 3.6–5.5 mo); EXE mono: 3.4 months (CI: 3.0–4.6 mo); No difference was recorded comparing the ANA+FULV vs the FULV+PLAC groups or between the FULV+PLAC and EXE monotherapy groups. |
NCT00075764 Phase III, randomised clinical trial | PMW with HR-pos MBC without prior therapy for MBC; prior adjuvant therapy with AI or TAM was allowed (following an early amendment). | 707 | Anastrozole | Fulvestrant | The median PFS was 13.5 months (95% CI: 12.1–15.1) for the ANA monotherapy arm vs 15.0 months (95% CI: 13.2–18.4) for the ANA+FULV arm (P=0.007); The median overall survival was 41.3 months (95% CI: 37.2–45.0) with ANA alone and 47.7 months (95% CI: 43.4–55.7) with ANA+FULV (P=0.049). |
VI. Studies combining AIs with alternative compounds | |||||
Exemestane±Etinostat trial Phase II, randomised, double-blind, placebo-controlled, ‘signal-finding’ clinical trial (Yardley et al, 2013) | PMW with ER-pos BC experiencing relapse following adjuvant therapy with a NSAI (at least for 12 months) or progression of MBC during a NSAI (given for at least 3 months). | 130 | Exemestane | Etinostat | Median PFS was 4.3 months in the EXE+ETI group vs 2.3 months in the EXE+PLAC group; HR 0.73, 95% CI: 0.50–1.07 (P=0.055); Median overall survival was 28.1 months in the EXE+ETI arm vs 19.8 months in the EXE+PLAC subgroup, HR 0.59, 95% CI: 0.36–0.97 (P=0.036). |
NCT00405938 Phase II, non-randomised clinical trial | PMW with HR-pos MBC without any previous therapy for MBC were eligible; HER2-pos and HER2neg patients could participate. | 79 | Anastrozole | Bevacizumab | Median TTP was 21 months for the combination ANA+BEV vs 9 months for the combination FULV+BEV; the overall response rates were 47% and 27%, respectively; both combinations were evaluated as feasible as first-line therapy for MBC and are currently tested in ongoing phase III trials. |
LEA-study Phase III, randomised, open-label, clinical trial | PMW with HR-pos/HER2-neg MBC; no prior therapy for MBC was allowed. | 380 | Letrozole or fulvestrant | Bevacizumab | Median PFS was 14.4 months in the ET-group (LET or FULV monotherapy) vs 19.3 months in the ET-B group (LET or FULV combined with BEV); HR 0.83, 95% CI: 0.65–1.06 (P=0.126); Overall response rate was 22% with ET vs 41% with ET-B, (P<0.001); TTF and OS were comparable in both arms. |
NCT00050141 Phase II, randomised, blinded, parallel-group study | PMW with HR-pos BC progressing on tamoxifen either as adjuvant therapy or first line for advanced disease (objective response or stable disease during TAM-therapy was mandatory in MBC patients), | 120 | Letrozole | Tipifarnib | Median TTP was 10.8 months for the LET monotherapy arm vs 5.6 months for the combination LET+TIP; the ORR was 30% in the LET+TIP arm vs 38% in the LET monotherapy arm. Clinical benefit rate: 49% for the LET+TIP subgroup and 62% for the LET monotherapy cohort. |
