. 2010 Aug 9;1:155–171. doi: 10.2147/ijwh.s5647

Table 1.

Selected clinical trials of trastuzumab in breast cancer

Design	Key eligibility criteria	Treatment schema	Endpoints	Outcomes
Advanced disease
Phase III, randomized; 469 patients enrolled³¹	HER2-overexpressing (IHC 2+ or 3+), previously untreated, metastatic breast cancer	No prior anthracycline Doxorubicin (A) 60 mg/m² (or epirubicin 75 mg/m²) plus cyclophosphamide (C) 600 mg/m² q 3 wk × 6 cycles ± trastuzumab (H) 4 mg/kg × 1, then 2 mg/kg weekly till disease progression Prior anthracycline Paclitaxel (T) 175 mg/m² q 3 wk × 6 cycles ± trastuzumab as above	1⁰ – TDP and incidence of adverse effects 2⁰ – ORR, DOR,TTF, and OS	Data below are median values in patients treated with chemotherapy + trastuzumab vs chemotherapy alone: TDP (7.4 mo vs 4.6 mo; P < 0.001) ORR (50% vs 32%; P < 0.001) DOR (9.1 mo vs 6.1 mo; P < 0.001) TTF (6.9 mo vs 4.5 mo; P < 0.001) OS (25.1 mo vs 20.3 mo; P = 0.046); calculation includes patients who received trastuzmab after disease progression on chemotherapy alone Patients with 3 + HER2 scores had greater benefit than 2 + tumors
				Adverse events associated with trastuzumab therapy: All cardiac toxic events: AC + H = 27% (39 of 143 patients) AC alone = 8% (11 of 135 patients) T + H = 13% (12 of 91 patients) T alone = 1% (1 of 95 patients)
				Chills and/or fever (25%) Infections (47% compared to 29% of patients treated with chemotherapy alone)
Phase II open-label, randomized, efficacy and safety as first-line therapy; 186 patients enrolled⁸²	HER2-overexpressing (3+ IHC or FISH-positive) metastatic breast cancer	Docetaxel (D) 100 mg/m² ± H same dose/schedule indicated above	1⁰ – ORR 2⁰ – TDP,TTF, DOR, OS, and safety profile	Data below are median values in patients treated with D + H vs D alone: ORR (61% [6 CRs, 7% and 50 PRs 54%] vs 34% [2 CRs, 2% and 30 PRs, 32%]; P = 0.0002) TDP (11.7 mo vs 6.1 mo; P = 0.0001) TTF (9.8 mo vs 5.3 mo; P = 0.0001) DOR (11.7 mo vs 5.7 mo; P = 0.009) OS (31.2 mo vs 22.7 mo; P = 0.0325)
			1⁰ – ORR 2⁰ – TDP,TTF, DOR, OS, and safety profile	Adverse events associated with trastuzumab therapy: Grade 3–4 neutropenia (32% vs 22%) Febrile neutropenia (23% vs 17%) Symptomatic cardiac event (1 patient)
Adjuvant therapy
HERA phase III open-label, randomized; 3388 evaluable patients⁸⁴	Patients with HER2-overexpressing (3+ IHC or FISH-positive) breast cancer and completion loco-regional and systemic neo-adjuvant and adjuvant therapy. All patients required to have normal LVEF	Randomization to: Observation (control); n = 1693 1 yr H 8 mg/kg, then 6 mg/kg q 3 wk; n = 1694 2 yr H, same dose/schedule; n = 1694	1⁰ – DFS 2⁰ – site of first DFS event, TDR, OS, and cardiac safety	Efficacy analysis, based on intention-to-treat principle, reported below compares patients assigned to 1 yr H vs control: DFS events (127 vs 220; P < 0.0001) TDR (HR 0.49; P < 0.0001) OS (96% vs 95.1%; P = 0.26)
				Cardiac events: Class III/IV heart failure (9 patients vs 0; P = 0.002) Symptomatic CHF including class III/IV (29 patients vs 1 patient; P < 0.001) Decrease in LVEF to < 50% (113 patients vs 34 patients; P < 0.001)
NSABP (B-31) and NCCTG (N9831) phase III open-label, randomized; 3351 evaluable patients⁶⁹	Patients with HER2-overexpressing (3+ IHC or FISH-positive) and node-positive or high-risk node-negative breast cancer. All patients required to have normal LVEF	B-31 randomization: A at 60 mg/m² + C at 600 mg/m² q 3 wk × 4 cycles followed by T at 175 mg/m² q 3 wk × 4 cycles AC followed by T+H at 4 mg/kg beginning with first dose of T, then 2 mg/kg weekly × 51 wk	1⁰ – DFS 2⁰ – TDR, OS, and death due to breast cancer or other second malignancy	For the analysis, combined data from groups 1 and A were compared to data from groups 2 and C; median follow-up was 2 yr DFS events (261 vs 133; P < 0.0001) TDR (HR 0.47; P < 0.0001) OS (94.3% vs 91.7%; P = 0.015) Death from breast cancer (79 patients vs 53 patients; P = 0.02) Death due to second primary (20 patients vs 5 patients; P = 0.002) Class III/IV CHF, 3 yr cumulative incidence (0% vs 2.9% of which one patient died of cardiac toxicity)
		N9831 randomization: AC at same doses/schedules followed by T at 80 mg/m² q wk × 12 wk As in “A” above followed by same dose and schedule of H As in “ A” above with H given concurrently beginning with first dose of T
FinHer Phase III randomized, open-label; 1010 patients enrolled⁸⁶	Patients, status post breast surgery, node-positive or high-risk node-negative, confirmed HER2 amplification by chromogenic in-situ hybridization	Randomization (4 arms): D at 100 mg/m² q 3 wk × 3 cycles ± 9 total doses of H at 4 mg/kg beginning with first dose of D, then 2 mg/kg weekly × 8 followed by 3 cycles of fluorouracil (F) 600 mg/m², epirubicin (E) 60 mg/m², cyclophosphamide (C) 600 mg/m² q 3 wk	1⁰ – RFS 2⁰ OS and cardio toxic events	*Analyses were limited to 232 (of 1010) patients who had an amplified HER2* gene; of the 232 women, 116 who received H are compared to 116 who did not** RFS at 3 yr (12 [10.7%] vs 27 [22.4%] patients with recurrence; P = 0.01) OS at 3 yr (6 [5.2%] vs 14 [12%] patients died; P = 0.07)
		Vinorelbine (V) 25 mg/m² days 1, 8, and 15 q 3 wk × 3 cycles ± H at same dose/schedule listed above followed by FEC as noted above	1⁰ – RFS 2⁰ OS and cardio toxic events	Cardiac events (3 LVEF < 50% and 1 myocardial infarction; none received H) RFS at 3 yr (HER2+ treated with H vs HER2–, no H; P = 0.82)
BCIRG 006 phase III randomized trial; 3222 evaluable patients⁹²	Patients with HER2-overexpressing (FISH-positive) and node-positive or high-risk node-negative breast cancer	Randomization: A at 60 mg/m² + C at 600 mg/m² q 3 wk × 4 cycles followed by D at 100 mg/m² q 3 wk × 4 cycles AC followed by D as noted above + H at 4 mg/kg beginning with first dose of D, then 2 mg/kg weekly × 51 wk D 75 mg/m² + carboplatin (C) AUC 6 q 3 wk × 6 cycles + H at dose/schedule noted above	1⁰ – DFS 2⁰ – OS and symptomatic cardiac events	2nd interim analysis of patients randomized to groups 1 (n = 1073), 2 (n = 1074), and 3 (n = 1075) with a median follow-up of 3 years; comparisons were made between H-containing regimens and group 1: DFS (88.1% [ACDH] and 86.8% [DCH] vs 82.1%; P < 0.0001 and P = 0.0003, respectively) OS (95.4% [ACDH] and 94.8% [DCH] vs 92.5%; P = 0.004 and P = 0.017, respectively) DFS and OS (no difference between H-containing groups)
			1⁰ – DFS 2⁰ – OS and symptomatic cardiac events	Symptomatic cardiac events (0.4% [ACD and DCH] vs 1.9% [ACDH])
Neoadjuvant therapy
NOAH Phase III randomized, open-label, evaluating addition of H to standard pre-operative chemotherapy; enrolled 228 patients⁸⁹	Patients with locally advanced HER2-positive breast cancer (T3N1 or any T plus N2 or N3 or ipsilateral supraclavicular node involvement)	Treatment randomization prior to surgery: 3 cycles of A at 60 mg/m² + T at 150 mg/m² q 3 wk, followed by 4 cycles of T at 175 mg/m² q 3 wk, followed by 3 cycles of (C at 600 mg/m², methotrexate at 40 mg/m², and fluorouracil at 600 mg/m²) on days 1 and 8 repeated q 4 wk Same regimen as noted above + H given concurrently with the beginning of A at 8 mg/kg load, then 6 mg/kg q 3 wk for 1 yr	1⁰ – EFS 2⁰ – cPR, ORR, and OS	Analysis compares H-containing regimen and chemotherapy alone; at a median follow-up of 3 years: EFS (70% vs 53%; P = 0.006) ORR (89% vs 77%; P = 0.02) PCR (39% vs 20%; P = 0.002) OS (not significant) Cardiac toxicity (95% of patients had common toxicity criteria values of 0–1)
Phase III prospective, randomized; target enrollment of 164 patients⁸⁷	Patients with stage II or IIIA locally advanced, noninflammatory HER2-positive (FISH-positive or 3+ IHC) breast cancer	Treatment randomization prior to surgery: 4 cycles of T at 225 mg/m² q 3 wk, followed by 4 cycles of F at 500 mg/m² days 1 and 4, E at 75 mg/m² day 1 only, and C at 500 mg/m² day 1 only, repeated q 3 wk Same regimen as noted above + H given concurrently with the beginning of T at 4 mg/kg load, then 2 mg/kg q wk for 23 wk	1⁰ – 20% improvement in pCR	Trial stopped after 34 patients had completed therapy because of superiority of the H-containing regimen pCR (66.7% vs 25%; P = 0.02). Cardiac events (no clinical CHF observed)
Phase II open-label trial; 33 patients enrolled⁸⁸	Patients with stage II or III locally advanced, non-inflammatory HER2-positive (3+ IHC) breast cancer	Treatment prior to surgery: H 4 mg/kg load, then 2 mg/kg q wk then D at 100 mg/m² q 3 wk for 6 cycles.	1⁰ – pCR 2⁰ – OR (CR and PR), BCS, DFS, local and distant relapse, and safety	Intention-to-treat analysis confined to 29 patients who completed therapy pCR (tumor and node, 47% of patients) OR (CR, 73%; PR 23%) BCS (23 [77%] patients) Grade 3–4 neutropenia (85% of patients) Febrile neutropenia (18% of patients) No cardiotoxic events

Abbreviations: BCS, breast-conserving surgery; CHF, coronary heart failure; cPR, complete pathologic response; EFS, event-free survival; HER2, human epidermal growth factor receptor 2; IHC, histochemistry; LVEF, left ventricular ejection fraction; NSABP, National Surgical Adjuvant Breast and Bowel Project; ORR, overall response rate; DOR, duration of response; TTF, time to treatment failure; ORR, overall response rate; OS, overall survival; RFS, recurrence-free survival; TDP, time to disease progression; TDR, time to distant recurrence.