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 | ||
