Table 1. Characteristics of the trials included in network meta-analysis.
| Study | Study Design | Median follow-up (mon) | Median age (yr) | HR+/N+(%) | Sample size | Treatment arm | Arms | Frequency and Dose of HER2-targted agents | Duration (wks) | Primary endpoints | Secondary endpoints |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NSABP-B31 | RCT, phase III | 87 | 49 | - | 1,736 | ACT | 743 | Trastuzumab (4 mg/kg loading, 2 mg/kg q. wk). | - | Cardiac event | - |
| ACT + H | 947 | 52 | |||||||||
| BCIRG-006 | RCT, phase III | 80.4 | 49 | 54/62 | 3,222 | ACT | 1,073 | Trastuzumab (4 mg/kg loading, 2 mg/kg q. wk during chemotherapy and then 6 mg/kg q. 3wk). | - | DFS | OS, Safety |
| 54/71 | ACT + H | 1,074 | 52 | ||||||||
| 54/72 | TC + H | 1,075 | |||||||||
| FinHer | RCT, phase III | 62 | 50.9 | - | 232 | ACT | 116 | Trastuzumab (4 mg/kg loading, 2 mg/kg q. wk). | - | RFS | OS, LVEF |
| ACT + H | 115 | 9 | |||||||||
| HERA | RCT, phase III | 132 | 49 | 50/57 | 5,102 | AC/TC/ACT | 1,697 | Trastuzumab (8 mg/kg loading, 6 mg/kg q. 3 wk). | - | DFS | OS, Cardiac safety |
| 51/57 | AC/TC/ACT-H | 1,702 | 52 | ||||||||
| 50/57 | AC/TC/ACT-H | 1,700 | 104 | ||||||||
| E2198 | RCT, phase II | 77 | 49 | 45/100 | 227 | ACT + H | 112 | Trastuzumab (4 mg/kg loading dose in week 1 followed by 2mg/kg weekly). | 52 | Cardiac toxicity | DFS, OS |
| 47/100 | ACT + H | 115 | 12 | ||||||||
| HORG | RCT, phase III | 51 | 54 | 64.7/74.6 | 481 | ACT + H | 241 | Trastuzumab (loading dose 6 mg/kg; 4 mg/kg q. 2 wk during chemotherapy, then 6 mg/kg q. 3 wk). | 52 | DFS | OS, Toxicity |
| 56 | 68.8/83.3 | ACT + H | 240 | 26 | |||||||
| NCCTG-N9831 | RCT, Phase III | 110.4 | 49 | - | 1,944 | ACT | 664 | Trastuzumab (4 mg/kg loading, 2 mg/kg q. wk). | - | DFS | - |
| ACT + H | 710 | 52 | |||||||||
| ACT-H | 570 | ||||||||||
| ShortHER | RCT, phase III | 72 | 55 | 68/47 | 1,253 | ACT + H | 627 | Trastuzumab (8 mg/kg loading dose at 1st cycle, and 6 mg/kg thereafter, q. 3 wk for 18 doses). | 52 | DFS, OS | Failure Rate, Cardiac Events |
| 68/46 | ACT + H | 626 | Trastuzumab (4 mg/kg loading dose at 1st wk, and 2 mg/kg weekly). | 9 | |||||||
| SOLD | RCT, phase III | 62.4 | 56 | 66(ER)/46(PR)/41 | 2,176 | ACT + H | 1,085 | Trastuzumab (iv.first dose 4mg/kg, subsequently 2mg/kg weekly or first dose 8 mg/kg, subsequently 6 mg/kg q. 3 wk) or (subcutaneously 600 mg regardless of body weight q. 3 wk during chemotherapy, then either iv. first dose 8 mg/kg, subsequently 6 mg/kg or subcutaneously 600mg regardless of body weight q. 3 wk 14 times). | 9 | DFS | DDFS, OS, Cardiac safety |
| 66(ER)/47(PR)/40 | ACT + H | 1,089 | 52 | ||||||||
| NCCTG-N9831+NSABP-B31 | RCT, phase III | 100.8 | - | 54.8/92.6 | 4,046 | ACT | 2,018 | Trastuzumab (initial loading dose 4 mg/kg, then 2 mg/kg weekly). | - | Cardiac event | - |
| 54.7/93.4 | ACT + H | 2,028 | 52 | ||||||||
| PACS-04 | RCT, phase III | 47 | 48 | 61/100 | 528 | AC/AT | 268 | Trastuzumab (8 mg/kg loading, 6 mg/kg q. 3 wk). | - | DFS | Safety, OS, EFS |
| 58/100 | AC/AT-H | 260 | 52 | ||||||||
| APHINITY | RCT, phase III | 45.4 | - | 64.3/62.4 | 4,805 | ACT/TC + H | 2,402 | Trastuzumab (8 mg/kg.iv as a loading dose, followed by 6 mg/kg.iv q. 3 wk) plus placebo (840 mg.iv as a loading dose, followed by 420 mg.iv q. 3 wk). | 52 | iDFS | OS, DFS, RFS, DRFS |
| 64/62.6 | ACT/TC + H + P | 2,400 | Trastuzumab (8 mg/kg.iv as a loading dose, followed by 6 mg/kg.iv q. 3 wk) plus pertuzumab (840 mg.iv as a loading dose, followed by 420 mg.iv q. 3 wk). | 52 | |||||||
| PHERSEPHONE | RCT, phase III | 64.8 | 56 | 69/42 | 4,089 | AC/TC/ACT + H | 2,045 | Trastuzumab (initial loading dose of 8 mg/kg followed by 6 mg/kg q. 3 wk intravenously or subcutaneously 600 mg). | 52 | DFS | OS, Cardiac Events, |
| 69/40 | AC/TC/ACT + H | 2,043 | 26 | ||||||||
| PHARE | RCT, phase III | 42.5 | 54 | 60.4/44.6 | 3,380 | AC/TC/ACT + H | 1,690 | Trastuzumab (initial loading dose of 8 mg/kg followed by 6 mg/kg q. 3 wk intravenously or subcutaneously 600 mg). | 52 | DFS | OS, Cardiac safety |
| 55 | 61.5/45.3 | AC/TC/ACT + H | 1,690 | 26 | |||||||
| ALTTO | RCT, phase III | 54 | 51 | 57/51 | 8,381 | ACT/TC + H | 2,097 | Trastuzumab (4 mg/kg once and then 2 mg/kg weekly during chemotherapy or 8 mg/kg once and then 6 mg/kg q. 3 wk). | 52 | DFS | OS, cardiac safety |
| 57/52 | ACT/TC + L | 2,100 | Oral lapatinib (750 mg/day during chemotherapy and 1,500 mg/day when given alone). | 52 | |||||||
| 57/51 | ACT/TC + H + L | 2,093 | Trastuzumab (12 weekly dose) plus Lapatinib (750 mg/day during chemotherapy, with an escalation to 1,000mg/day at chemotherapy completion). | 52 | |||||||
| 58/52 | ACT/TC + H-L | 2,091 | Trastuzumab (12 weekly dose) followed after a 6-wk washout by oral Lapatinib (1,500 mg/day, 34 wk). | 52 | |||||||
| TEACH | RCT, phase III | 47.4 | 52 | 59/54 | 3,161 | AC/TC/ACT | 1,576 | Oral placebo (1,500 mg) daily. | 52 | DFS | OS, Toxic effects |
| 51 | 59/54 | AC/TC/ACT + L | 1,571 | Oral lapatinib (1,500 mg) daily. | 52 | ||||||
| ExteNet | RCT, phase III | 62.4 | 52 | 57/77 | 2,840 | AC/TC/ACT + H | 1,420 | Oral neratinib (240 mg) or placebo daily, administered after chemotherapy and trastuzumab | 52 | iDFS | DFS, DDFS, OS, Safety |
| 57/77 | AC/TC/ACT + H-N | 1,420 |
HR+ = hormone receptor positive; N+ = lymph node positive; RCT = randomized clinical trial; ACT = anthracycline-, cyclophosphamide- and taxane-based chemotherapy regimen; TC = taxane-based chemotherapy regimen; AC = anthracycline based chemotherapy regimen; H = trastuzumab; L = lapatinib; N = netatinib; P = pertuzumab; + = concurrently administration; - = sequentially administration; q. wk = every week; q. 3 wk = every 3 weeks; q. 2 wk = every 2 weeks; DFS = disease free survival; OS = overall survival; DDFS = distant disease free survival; iDFS = invasive disease free survival; EFS = event free survival; RFS = recurrence free survival; LVEF = left ventricular ejection fraction.