Table 2.
Clinical data from patients with breast cancer (organized by neoadjuvant, extended adjuvant, metastatic).
| Article | Trial type/indication | ER-targeting agent | HER2-targeting agent | Other agent | Key summaries | ||
|---|---|---|---|---|---|---|---|
| Neoadjuvant | |||||||
| Masuda 201893 |
Open label phase II (Neo-LaTH) Invasive breast cancer, neoadjuvant (n = 215) |
Leuprorelin 11.25 mg (weeks 1-13) + TAM 20 mg/day or letrozole 2.5 mg/day | Lapatinib (1000 mg/day initially, then 750 mg/day), trastuzumab (4 mg/kg in Week 1 and then 2 mg/kg) | Paclitaxel (80 mg/m2) |
Japanese patients; HER2+ • Lapatinib + trastuzumab followed by lapatinib + trastuzumab + paclitaxel with or without prolongation of anti-HER2, with or without ET ○ 47.9% achieved CpCR (ER−, 63.0%; ER+, 36.1%; P = 0.0034) ○ 42.2% achieved pCR with pN0 (ER−, 57.6%; ER+, 30.3%) |
||
| Harbeck 201791 |
Open label phase II (WGSG ADAPT) Early breast cancer, neoadjuvant (n = 375) |
TAM or AI | T-DM1 (3.6 mg/kg) and trastuzumab (8 mg/kg loading, then 6 mg/kg) | None |
HER2+/HR+ • T-DM1 vs. T-DM1 + ET vs. trastuzumab + ET pCR at 12 weeks, 41.0% vs. 41.5% vs. 15.1% (P < 0.001) |
||
| Prat Aparicio 201792 |
Open label phase II (PAMELA) Stage I-IIIA HER2+ breast cancer, neoadjuvant (n = 151) |
Letrozole or tamoxifen | Lapatinib and trastuzumab | None |
HER2+ • Overall pCR at 18 weeks was 30.5% (HR+, 18.2%; HR−, 43.2%) • Rate of pCR was 40.6% in HER2-E and 10.0% in non–HER2-E (P < 0.0001) • Within HR+ disease, pCR rates were 31.6% in HER2-E and 5.3% in non–HER2-E (P = 0.006) Within HR− disease, pCR rates were 46.0% in HER2-E and 27.3% in non–HER2-E (P = 0.331) |
||
| Gluz 202090 |
Open label, phase II (WSG TP-II) HR+/HER2+ EBC, neoadjuvant (n = 207) |
Standard ET | Trastuzumab and pertuzumab | Paclitaxel 80 mg/m2 |
HR+/HER2+ • ET+ trastuzumab + pertuzumab vs. paclitaxel + trastuzumab + pertuzumab • pCR (at 12 weeks), was 24% vs. 57% (P < 0.001) |
||
| Gianni 201869 |
Open label phase II (NA-PHER2) Invasive breast cancer, neoadjuvant (n = 36) |
Fulvestrant 400 mg (SERD) | Trastuzumab (8 mg/kg loading, then 6 mg/kg) and pertuzumab (800 mg loading then 420 mg; mAb) | Palbociclib 125 mg/day (checkpoint inhibitor) |
ER+/HER2+ • Change in mean Ki67 expression ○ At BL, 31.9 ○ At 2 weeks, 4.3 (P < 0.0001) ○ At time of surgery, 12.1 (P = 0.013) • Change in apoptosis from BL to surgery ○ 1.2−0.4 (P = 0.019) • Presurgery objective response in 29/30 (97%) patients |
||
| Park 201678 |
Open label phase II (Neo-ALL-IN) Stage II-III breast cancer, neoadjuvant (n = 24) |
Letrozole 2.5 mg/day (non-steroidal AI) | Lapatinib 1500 mg/day (TKI) | None |
Asian patients; ER+/HER2+ tumors • Clinical overall response rate, 62.5% (1 CR; 0 pCR) • Potential biomarkers: TILs, ER expression, IHC ER Allred score, 18F-FES PET-CT |
||
| Rimawi 201371 |
Open label phase II (TBCRC 006) Stage II-III breast cancer, neoadjuvant (n = 64) |
Letrozole (non-steroidal AI) | Lapatinib 1000 mg/day (TKI) and trastuzumab (4 mg/kg loading, then 2 mg/kg; mAb) | None |
Stage II-III, HER2+; ER+ (n = 40) • In-breast pCR, 27% (ER+ , 21%; ER−, 36%) • Overall pathologic response rate, 49% • Low-volume residual disease rate, 22% (ER+, 33%; ER−, 4%) |
||
| Rimawi 202094 |
Open label phase II (TBCRC023) Stage II-III breast cancer, neoadjuvant (n = 97) |
Letrozole 2.5 mg/day (non-steroidal AI) | Lapatinib 1000 mg/day (TKI) and trastuzumab (4 mg/kg loading, then 2 mg/kg) | None |
Stage II-III, HER2+ (n = 97) • 12 vs. 24 weeks of lapatinib + trastuzumab (+ letrozole if ER+) ○ 12-week pCR, 12% (ER+, 9%; ER−, 20%) ○ 24-week pCR, 28% (ER+, 33%; ER−, 18%) |
||
| Guarneri 201435 |
Phase IIb RCT Stage II-IIIA breast cancer, neoadjuvant/adjuvant (n = 92) |
Letrozole 2.5 mg/day (non-steroidal AI) | Lapatinib 1500 mg/day (TKI) | None |
HR+/HER2− • Letrozole + lapatinib vs. letrozole alone ○ Clinical response rate (CR + PR), 70% vs. 63% ○ Ki-67 and pAkt expression were significantly decreased from BL to surgery in both arms ○ ORR in patients with PIK3CA mutation, 93% vs. 63% (P = 0.04) |
||
| Rimawi 201776 |
Phase III RCT (NSABP B-52) Breast cancer in the neoadjuvant setting (n = 315) |
AI | Trastuzumab and pertuzumab | Docetaxel, carboplatin, estrogen deprivation (goserelin and AI) |
HR+/HER2+ • TCHP + estrogen deprivation therapy vs. TCHP alone ○ pCR (breast and nodes), 46.1% vs. 40.9% (P = 0.36) ○ pCR (breast), 47.4% vs. 44.2% (P = 0.57) |
||
| Extended adjuvant | |||||||
|
Chan 20167 Martin 201779 Chan 202189 |
Phase III RCT (ExeteNET) Stage I-IIIc operable breast cancer, post-adjuvant (n = 2,840) |
None | Neratinib 240 mg/day (TKI) after trastuzumab (mAb)–based neoadjuvant and adjuvant therapy | None |
HER2+ • Neratinib vs. placebo ○ iDFS events at 2 years, 70 vs. 109 events (hazard ratio, 0.67; P = 0.0091) ○ iDFS events at 5-year follow-up, 116 vs. 163 events (hazard ratio, 0.73; P = 0.0083) ○ DFS rate at 2 (93.9% vs. 91.6%) and 5 (90.2% vs. 87.7%) years ○ DFS benefit with neratinib was observed in HR+ patients, but not in HR− ○ OS rate at 8 years, 91.3% vs 82.2% (hazard ratio, 0.47) |
||
| Tolaney 202182 |
Phase III RCT (eMonarcHER) High-risk breast cancer (planned n = 2450) |
Standard ET None |
Abemaciclib 150 mg (CDK4/6 inhibitor) | None | • Planned to start | ||
| Dieci 202288 |
Phase III (Short-HER) HER2+/HR+ early breast cancer (n = 1254) |
AI and/or TAM | Trastuzumab | Anthracycline-taxane chemotherapy |
HER2+/HR+ • 9 weeks vs. 1 year of adjuvant trastuzumab + anthracycline-taxane chemotherapy + adjuvant ET • 7-year DFS with AI was 87.3% vs. 81.7% with TAM or TAM-AI (hazard ratio, 1.46; log-rank P = 0.017) |
||
| Advanced/metastatic | |||||||
| Jhaveri 202287 |
Open label phase II (SUMMIT) Metastatic breast cancer and prior CDK4/6i (n = 55) |
Fulvestrant 500 mg | Neratinib (240 mg/day), trastuzumab (8 mg/kg initially, then 6 mg/kg) | None |
HR+, HER2− • Neratinib + trastuzumab + fulvestrant (n = 45) ○ ORR, 38% ○ Median DOR, 14.4 months ○ Clinical benefit, 47% ○ Median PFS, 8.2 months |
||
| Ciruelos 202086 |
Open label phase II (PATRICIA) Advanced breast cancer (n = 71) |
Letrozole | Palbociclib (200 mg/day), trastuzumab (8 mg/kg loading, then 6 mg/kg IV or 600 mg SC) | None |
HER2+ • Palbociclib + trastuzumab (ER−) ○ 6-month PFS, 33.3% • Palbociclib + trastuzumab (ER+) ○ 6-month PFS, 42.8% • Palbociclib + trastuzumab + letrozole (ER+) ○ 6-month PFS, 46.4% |
||
| Hua 202285 |
Open label phase III (SYSUCC-002) Metastatic breast cancer (n = 392) |
Investigator’s choice ET (ER modulator or AI) | Trastuzumab (8 mg/kg loading, then 6 mg/kg) | Chemotherapy (investigator’s choice of taxanes, capecitabine, or vinorelbine) |
Patients in China, HER2+ • Trastuzumab + ET vs. trastuzumab + chemotherapy ○ Median PFS, 19.2 vs. 14.8 months (P < 0.0001) |
||
| Swain 202084 |
Phase III RCT (CLEOPATRA) Metastatic breast cancer (n = 808) |
None | Trastuzumab (8 mg/kg loading, then 6 mg/kg) and pertuzumab (840 mg loading, then 420 mg) | Docetaxel (75 mg/m2 escalating to 100 mg/m2 if tolerated) |
HER2+ • Trastuzumab + docetaxel + pertuzumab ○ Median OS, 57.1 months ○ 8-year OS rate, 37% • Trastuzumab + docetaxel + placebo ○ Median OS, 40.8 months ○ 8-year OS rate, 23% |
||
| Chu 200874 |
Open label phase I Advanced solid tumors (n = 34) |
Letrozole 2.5 mg/day (non-steroidal AI) | Lapatinib 1250–1500 mg/day (TKI) | None |
HR+ (n = 18) • In the breast cancer cohort: ○ PR, n = 1 ○ SD, n = 2 (lasting 247 and 289 days) • Well tolerated • No pharmacokinetic interaction |
||
| Fumoleau 201477 |
Open label phase I Metastatic breast cancer (n = 23) |
Tamoxifen 20 mg/day (SERM) | Lapatinib 1500 mg/day (TKI) | None |
HR+ irrespective of HER2 status • SD, 8/23 (36.4%) • Median PFS, 2.7 months • Well tolerated |
||
| Koeberle 201175 |
Open label phase I AI- and trastuzumab-resistant breast cancer (n = 13) |
Letrozole (non-steroidal AI) | Trastuzumab (mAb) | None |
ER+/HER2+ breast cancer • Trastuzumab alone (step 1) then trastuzumab + letrozole upon disease progression (step 2) • CBR (primary outcome) ○ Step 1, 46% ○ Step 2, 73% • Median TTP 188 days |
||
| Shagisultanova 201980 |
Phase Ib/II trial Metastatic breast cancer (n = 20) |
Letrozole 2.5 mg/day (non-steroidal AI) | Tucatinib 300 mg BID (TKI) | Palbociclib 125 mg/day (CDK4/6 inhibitor) |
• Safety consistent with previous reports • Longest time on trial is 10 months (no CNS disease at BL) and 6 months (CNS disease at BL) Recommended phase II dose is tucatinib 300 mg bid |
||
| Marcom 200770 |
Open label phase II Advanced breast cancer (n = 31) |
Letrozole (non-steroidal AI) | Trastuzumab (mAb) | None |
ER+ and/or PR+ and HER2+ • Overall response rate, 26% • CBR, 52% • Median TTP, 5.5 months • Median DOR, 20.6+ months |
||
|
Ma 202197 Ma 202283 |
Open label phase II (MutHER) Metastatic breast cancer (n = 31) |
Fulvestrant | Neratinib 240 mg/day (TKI) | None |
Patients with prior fulvestrant treatment • ORR, 25% • SD (≥24 weeks), 15% • Median PFS, 24 weeks • CBR, 38% Fulvestrant-naïve patients • ORR, 30% • SD (≥ 24 weeks), 0 • Median PFS, 20 weeks • CBR, 30% Exploratory ER− cohort • CBR, 25% |
||
| Villanueva 201372 |
Open label phase II Metastatic breast cancer (n = 24) |
Letrozole 2.5 mg/day (non-steroidal AI) | Lapatinib 1500 mg/day (TKI) | None |
AI-resistant, HR+ breast • ORR (at 12 weeks), 4% • SD, 25% • CBR, 21% • Median PFS, 3.4 months |
||
| Smyth 202096 |
Open label phase II (SUMMIT) Metastatic breast cancer (n = 81) |
Fulvestrant 500 mg every 4 weeks (SERD) | Neratinib 240 mg/day (TKI) | None |
Neratinib monotherapy vs. neratinib + fulvestrant (70 patients with ER+/HER2+ tumors) • ORR, 17.4% vs. 14.0% • CBR, 30.4% vs. 46.8% • Median PFS, 3.6 vs. 5.4 months |
||
| Rimawi 201838 |
Phase II RCT (PERTAIN) Metastatic or locally advanced breast cancer (n = 129) |
Anastrozole 1 mg/day or letrozole 2.5 mg/day (non-steroidal AI) | Trastuzumab (8 mg/kg loading, then 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading, then 420 mg every 3 weeks; mAb) | Induction chemotherapy allowed |
HR+/HER2+ • Pertuzumab + trastuzumab + AI vs. trastuzumab + AI ○ Median PFS (stratified by induction chemotherapy), 18.89 vs. 15.80 months (hazard ratio, 0.66; P = 0.007) ○ CR, 7.3% vs. 0.9% ○ CBR, 68.8% vs. 67.0% ○ Median DOR for CR/PR, 27.10 vs. 15.11 months |
||
| Huober 201273 |
Phase III open label (eLEcTRA) Metastatic breast cancer (n = 57) |
Letrozole 2.5 mg/day (non-steroidal AI) | Trastuzumab (4 mg/kg loading, then 2 mg/kg; mAb) | None |
HR+/HER2+; HR+/HER2−(n = 35) • Letrozole + trastuzumab vs. letrozole alone ○ Median TTP, 14.1 vs. 3.3 months (hazard ratio, 0.71; P = 0.03) ○ CBR, 65% vs. 39% (odds ratio, 2.99; P = 0.0636) ○ ORR,13% vs. 27% |
||
|
Johnston 200965 Schwartzberg 201066 |
Phase III RCT (EGF30008) Metastatic breast cancer (N = 1,286) |
Letrozole 2.5 mg/day (non-steroidal AI) | Lapatinib 1500 mg/day (TKI) | None |
HR+/HER2+ (n = 219) • Letrozole + lapatinib vs. letrozole alone ○ Median PFS, 8.2 vs. 3.0 months (hazard ratio, 0.71; P = 0.019) ○ CBR, 48% vs. 29% (odds ratio, 0.4; P = 0.003) ○ ORR, 28% vs. 15% (odds ratio, 0.4; P = 0.021) ○ Median OS, 33.3 vs. 32.3 months |
||
| Kaufman 200967 |
Phase III RCT (TAnDEM) Metastatic breast cancer (n = 207) |
Anastrozole 1 mg/day (non-steroidal AI) | Trastuzumab (4 mg/kg loading, then 2 mg/kg every week) (mAb) | None |
HR+/HER2+ • Anastrozole + trastuzumab vs. anastrozole alone ○ Median PFS, 4.8 vs. 2.4 months (hazard ratio, 0.63; P = 0.0016) ○ Median OS, 28.5 vs. 23.9 months (P = 0.325) ○ 70% of patients in the anastrozole-alone arm crossed over to combination therapy after progression ○ Median TTP, 4.8 vs. 2.4 months (P = 0.0007) ○ CBR, 42.7% vs. 27.9% (P = 0.026) ○ Median DOR, 9.5 vs. 10.0 months |
||
| Johnston 202195 |
Phase III RCT (ALTERNATIVE) Metastatic breast cancer (n = 355) |
Letrozole, anastrozole, or exemestane (non-steroidal or steroidal AI) | Lapatinib and trastuzumab (mAb) | None |
HR+/HER2+ • Lapatinib + trastuzumab plus AI vs. trastuzumab + AI ○ Median PFS, 11.0 vs. 5.7 months (hazard ratio, 0.62; P = 0.0064) ○ Overall response rate, 31.7% vs. 13.7% ○ CBR, 41% vs. 31% • Lapatinib + AI vs. trastuzumab + AI ○ Median PFS, 8.3 vs. 5.7 months (hazard ratio, 0.71; P = 0.0361) ○ Overall response rate, 18.6% vs. 13.7% ○ CBR, 33% vs. 31% |
||
| Tolaney 202037 |
Open label phase II (monarchHER) Metastatic breast cancer (n = 237) |
Fulvestrant 500 mg (SERD) | Trastuzumab (mAb) | Abemaciclib 150 mg (CDK4/6 inhibitor) |
• No chemotherapy • Tolerable safety profile • PFS for abemaciclib, trastuzumab, and fulvestrant vs. standard-of-care chemotherapy and trastuzumab (8.3 vs. 5.7 months, 5.4–7.0; hazard ratio, 0.67 [95% CI, 0.45–1.00]; P = 0.051) |
||
| Zhang 202181 |
Phase Ib/II trial Metastatic breast cancer (n = 15) |
Letrozole 2.5 mg/day (non-steroidal AI) | Pyrotinib 400 mg/day (TKI) | SHR6390 150 mg/day (CDK4/6 inhibitor) |
• Ongoing • 10 of 15 patients had achieved confirmed PRs |
||
Italic text indicates gene names.
18F-FES PET-CT 18F-fluoroestradiol positron emission tomography combined with computed tomography, AI aromatase inhibitor, BID twice daily, BL baseline, CBR clinical benefit rate, CNS central nervous system, CpCR comprehensive pathological complete response, CR complete response, DFS disease-free survival, DOR duration of response, EBC early breast cancer, ER estrogen receptor, ET endocrine therapy, HER2 human epidermal growth factor receptor 2, HER2-E HER2-enriched, HR hormone receptor, iDFS invasive disease-free survival, IHC immunohistochemical, mAb monoclonal antibody, ORR objective response rate, OS overall survival, pCR pathologic complete response, PFS progression-free survival, pN0 pathologically node negative, PR partial response, RCT randomized controlled trial, SERD selective estrogen receptor degrader, SD stable disease, SERM selective estrogen receptor modulator, TAM tamoxifen, TCHP docetaxel, carboplatin, trastuzumab, and pertuzumab, T-DM1 trastuzumab emtansin, TKI tyrosine kinase inhibitor, TTP time to progression.