Table 1 Summaries of major clinical phase 2/3 trials on TKIs for breast cancer
From: Neratinib for HER2-positive breast cancer with an overlooked option
Study | Registration no. | Cancer type | Country | Trial phase (start year) | No. of subjects | Treatment | Outcome |
|---|---|---|---|---|---|---|---|
Awada A, et al. | NCT00706030 | Metastatic HER2-positive breast cancer; advanced solid tumors | The US | Phase 1/2 (2013) | 92 | Neratinib (160 or 240Â mg/day, orally) plus vinorelbine (25Â mg/m2, intravenously; days 1 and 8 of each 21-day cycle) | MTD: 240Â mg/day ORR: 41% (without prior lapatinib); 8% (with prior lapatinib). |
Chow LW, et al. | NCT00445458 | HER2-positive metastatic breast cancer; advanced malignant solid tumors | The US | Phase 1/2 (2013) | 110 | Neratinib (160 or 240Â mg/day orally) plus paclitaxel (80Â mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) | MTD: 240Â mg/day ORR: 73% Median PFS: 57 weeks |
Saura C, et al. | NCT00741260 | HER2-positive metastatic breast cancer | The US | Phase 1/2 (2014) | 105 | Neratinib (160, 200, or 240Â mg/day orally) plus capecitabine (1500 or 2000Â mg/m2 orally per day on days 1 to 14 of a 21-day cycle) | MTD: 240Â mg/day ORR: 64% (without previous lapatinib); 57% (with previous lapatinib) Median PFS: 40.3 weeks (without previous lapatinib); 35.9 weeks (with previous lapatinib) |
Burstein HJ, et al. | NCT00300781 | Advanced HER2-positive breast cancer | Multinational | Phase 2 (2010) | 136 | Neratinib 240Â mg/day orally | ORR: 24% (with prior trastuzumab); 56% (without prior trastuzumab) Median PFS: 22.3 weeks (with prior trastuzumab); 39.6 weeks (without prior trastuzumab) |
Martin M, et al. | NCT00777101 | Advanced HER2-positive breast cancer | Multinational | Phase 2 (2013) | 233 | Neratinib 240 mg/day orally monotherapy vs. lapatinib (1250 mg/day) plus capecitabine (2000 mg/m2/day on days 1–14 of each 21-day cycle) | Median OS: 19.7 vs. 23.6 months Median PFS: 4.5 vs. 6.8 months ORR: 29% vs. 41% |
Freedman RA, et al. | NCT01494662 (TBCRC 022) | HER2-Positive breast cancer and brain metastases | Multinational | Phase 2 (2016) | 40 | Neratinib 240Â mg/day orally | ORR: 8% Median OS: 8.7 months Median PFS:1.9 months |
Park JW, et al. | NCT01042379 | Early breast cancer | The US | Phase 2 (2016) | 193 | Neratinib 240 mg/day orally vs. trastuzumab (loading dose of 4 mg/kg intravenously for the first cycle, followed by maintenance dose of 2 mg/kg for cycles 2–12) | pCR rate: 56% vs. 33% |
Awada A, et al. | NCT00915018 (NEfERT-T) | Metastatic HER2-positive breast cancer | Multinational | Phase 2 (2009) | 479 | Neratinib (240Â mg/day orally) or trastuzumab (4Â mg/kg then 2Â mg/kg intravenously weekly), each combined with paclitaxel (80Â mg/m2 intravenously on days 1, 8, and 15 every 28 days) | Median PFS: 12.9 vs. 12.9 months ORR: 74.8% vs. 77.6% CBR: 88.4% vs.85.2% Median DOR: 13.4 vs. 12.9 months Incidence of CNS recurrence: 8.3% vs. 17.3% |
Jacobs SA, et al. | NCT01008150 (NSABP FB-7) | Locally advanced HER2-positive breast cancer | Multinational | Phase 2 (2011) | 126 | Arm 1: Paclitaxel (80Â mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle) with trastuzumab (4Â mg/kg intravenously as loading dose, and then 2Â mg/kg weekly for a total of 16 doses) Arm 2: Paclitaxel (80Â mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle), and neratinib (240Â mg/day orally) Arm 3: Trastuzumab and paclitaxel were intravenously given as in Arm 1, and neratinib (200Â mg/day orally) | pCR rate: 38% vs. 33% vs. 50% |
Chan A, et al. | NCT00878709 (ExteNET) | Early stage HER2-positive breast cancer | Multinational | Phase 3(2009) | 2840 | Neratinib (240Â mg once daily orally) vs. placebo | 2-year iDFS: 93.9% vs. 91.6% 5-year iDFS: 90.2% vs. 87.7% |
Saura C, et al. | NCT01808573 (NALA) | Metastatic HER2-positive breast cancer | Multinational | Phase 3(2013) | 621 | Neratinib (240Â mg once daily orally) plus capecitabine (750Â mg/m2 orally twice a day for 14 days of a 21-day cycle) with loperamide prophylaxis, or lapatinib (1250Â mg once daily orally) plus capecitabine (1000Â mg/m2 orally twice a day for 14 days of a 21-day cycle) | Mean PFS: 8.8 vs. 6.6 months Median PFS: 5.6 vs. 5.5 months Mean OS: 24.0 vs. 22.2 months Intervention for CNS disease: Cumulative incidence: 22.8% vs. 29.2% ORR: 32.8% vs. 26.7% Median DOR: 8.5 vs. 5.6 months |
Geyer CE, et al. | NCT00078572 | HER2-positive advanced breast cancer | The US | Phase 3(2004) | 324 | Combination therapy (lapatinib at a dose of 1250Â mg per day continuously plus capecitabine at a dose of 2000Â mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500Â mg per square meter on days 1 through 14 of a 21-day cycle) | Median PFS: 8.4 vs. 4.4 months |
Goss PE, et al. | NCT00374322 | HER2-positive early breast cancer | Multinational | Phase 3(2006) | 3161 | Daily lapatinib (1500Â mg) or daily placebo | Median DFS: 47.4 vs. 48.3 months |
Baselga J, et al. | NCT00553358 (NeoALTTO) | HER2-positive early breast cancer | Multinational | Phase 3(2008) | 455 | Oral lapatinib (1500Â mg), intravenous trastuzumab (loading dose 4Â mg/kg, subsequent doses 2Â mg/kg), or lapatinib (1000Â mg) plus trastuzumab for the first 6 weeks; weekly paclitaxel (80Â mg/m2) was then added to the regimen for a further 12 weeks | pCR rate: 51.3% vs. 29.5% |
Ma F, et al. | NCT02422199 | HER2-positive metastatic breast cancer | China | Phase 2 (2015) | 128 | 400Â mg pyrotinib or lapatinib 1250Â mg orally once per day for 21-day cycles in combination with capecitabine (1000Â mg/m2 orally twice per day on days 1 to 14) | ORR: 78.5% vs. 57.1% Median PFS: 18.1 vs. 7.0 months |
Yan M, et al. | NCT02973737 (PHENIX) | HER2-positive metastatic breast cancer | China | Phase 3 (2016) | 279 | Pyrotinib or placebo (400 mg, qd) plus capecitabine (1,000 mg/m2, bid on days 1–14) for 21-day cycles | Median PFS: 11.1 vs. 4.1 months |
Xu B, et al. | NCT03080805 (PHOEBE) | HER2-positive metastatic breast cancer | China | Phase 3 (2017) | 267 | Pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle | Median PFS: 12.5 vs. 6.8 months |
Kim et al. | NCT02418689 (NOV120101-203 trial) | HER2-positive metastatic breast cancer | South Korea | Phase 2 (2015) | 106 | 12Â mg poziotinib once daily on a 14-day on/7-day off schedule | Median PFS: 4.04 months |
Curigliano G, et al. | NCT02614794 | HER2-positive metastatic breast cancer | Multinational | Phase 3 (2015) | 612 | Tucatinib (oral; 300 mg twice daily), trastuzumab (6 mg/kg every 3 weeks), plus capecitabine (1000 mg/m2 twice daily on days 1–14 every 21 days) | Median OS: 24.7 vs. 19.2 months 2-year OS rate: 51% vs. 40% Median PFS: 7.6 vs. 4.9 months 1-year PFS rate: 29% vs. 14% |