Table 1 Summary of design and results of studies assessing first-line therapies for the treatment of patients diagnosed with HER2-positive metastatic breast cancer

Slamon 2001

Slamon et al. [1]

2001

Women with progressive mBC that overexpressed HER2 who had not previously received chemotherapy for metastatic disease

Chemotherapy once every 3 weeks for six cycles + trastuzumab loading dose 4 mg/kg on day 1, then 2 mg/kg every week until PD

Chemotherapy alone once every 3 weeks for six cycles

TTP

234

235

25.1

20.3

0.80 (0.64–1.00), p = 0.046

6.9

4.5

0.58 (0.47–0.70), p < 0.001

JO17360

Inoue et al. [16]

2009

Women with HER2-positive mBC, measurable lesion(s) fulfilling RECIST criteria, ECOG-PS 0–1, and LVEF > 50 %

Trastuzumab loading dose 4 mg/kg then 2 mg/kg every week + docetaxel 60 mg/m2 every 3 weeks

Trastuzumab loading dose 4 mg/kg then 2 mg/kg every week until PD followed by trastuzumab loading dose 4 mg/kg then 2 mg/kg every week + docetaxel 60 mg/m2 every 3 weeks

PFS; OS

53

54

NA

NA

NA

14.6

3.7

4.24 (2.48, 7.24), p < 0.01

EGF104535

Guan et al. [15]

2013

Women with newly diagnosed HER2-positive mBC (no prior treatment for metastatic disease was allowed, with the exception of hormonal treatment for patients with hormone receptor–positive disease; prior trastuzumab and/or taxane as neoadjuvant or adjuvant therapy were permitted provided therapy was completed 12 months before study entry)

Lapatinib (1500 mg/d) + paclitaxel (80 mg/m2 once per week for 3 weeks every 4 weeks)

Placebo once per day + paclitaxel (80 mg/m2 once per week for 3 weeks every 4 weeks)

OS

222

221

27.8

20.5

0.74 (0.58, 0.94), p = 0.0124

9.7

6.5

0.52 (0.42, 0.64), p = 0.001

MA.31

Gelmon et al. [31]

2015

Women with HER2-positive mBC, ECOG-PS 0–2, no prior therapy with cytotoxics or biologics for recurrent or advanced disease, baseline LVEF ≥ 50 %, measurable or nonmeasurable disease defined by RECIST (v1.0) criteria, and no major end-organ disease

Lapatinib (1250 mg/d) + taxane (paclitaxel 80 mg/m2 once per week on days 1, 8, and 15 of a 28-day schedule or docetaxel 75 mg/m2 once every 3 weeks) for 24 weeks followed by lapatinib (1,500 mg/d) until PD

Trastuzumab + taxane (once per week [4 mg/kg bolus followed by 2 mg/kg maintenance] + once per week paclitaxel; or once every 3 week [8 mg/kg bolus followed by 6 mg/kg maintenance] + docetaxel once every 3 weeks) for 24 weeks followed by trastuzumab (6 mg/kg once every 3 weeks) until PD

PFS

326

326

NA

NA

1.28 (0.95, 1.72), p = 0.11

9.0

11.3

1.37 (1.13, 1.65), p < 0.001

TAnDEM

Kaufman et al. [18]

2009

Postmenopausal women with HER2-positive and hormone receptor–positive mBC; LVEF > 50 %; ECOG-PS 0–1; and measurable or evaluable disease; prior chemotherapy for mBC or adjuvant chemotherapy within 6 months was not permitted

Anastrozole 1 mg/day + trastuzumab loading dose 4 mg/kg on day 1, then 2 mg/kg every week until PD

Anastrozole 1 mg/day until PD

PFS

103

104

28.5

23.9

p = 0.325

4.8

2.4

0.63 (0.47, 0.84), p = 0.0016

EGF30008

Johnston et al. [17]; Schwartzberg et al. [20]

2009

Postmenopausal women with histologically confirmed stage IIIB/IIIC or IV ER-positive and/or PgR–positive invasive breast cancer; LVEF within the range of normal; ECOG-PS 0–1. No prior therapy for advanced or metastatic disease was allowed

Lapatinib 1500 mg and letrozole 2.5 mg daily until PD

Letrozole 2.5 mg daily with matching lapatinib placebo pill until PD

PFS

111

108

33.3

32.3

0.74 (0.5, 1.1), p = 0.113

8.2

3

0.71 (0.53, 0.96), p = 0.019

Robert 2006

Robert et al. [19]

2006

Women (≥18 years old) with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive mBC; ECOG-PS 0–2. Patients could not have received prior chemotherapy for mBC

Carboplatin AUC = 6 + paclitaxel 175 mg/m2 every 3 weeks for six cycles trastuzumab 4 mg/kg loading dose, then 2 mg/kg weekly until PD

Paclitaxel 175 mg/m2 every 3 weeks for six cycles + trastuzumab 4 mg/kg loading dose, then 2 mg/kg weekly until PD

ORR

98

98

35.7

32.2

0.9 (0.88, 0.92), p = 0.76

10.7

7.1

0.66 (0.59, 0.73), p = 0.03

HERNATA Study

Andersson et al. [12]

2010

Women (18 to 75 years old) with HER2-positive mBC or LABC; ECOG-PS ≤ 2; normal LVEF. Prior chemotherapy and HER2-targeted treatment was not allowed for treatment of metastatic or locally advanced disease

Vinorelbine 30 or 35 mg/m2 on days 1 and 8 every 3 weeks until PD + trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks until PD

Docetaxel 100 mg/m2 every 3 weeks until PD + trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks until PD

TTP

141

143

38.8

35.7

1.01 (0.71, 1.42), p = 0.98

15.3

12.4

0.94 (0.71, 1.25), p = 0.67

BCIRG 007 Study

Valero et al. [22]

2010

Women (18 to 75 years old) with HER2-amplified mBC, either measurable lesions (RECIST criteria) or nonmeasurable disease including at least two radiologically evident lytic bone lesions, and a Karnofsky performance status ≥60 %. Patients were not eligible if they had received prior platinum salt therapy, chemotherapy, or trastuzumab for mBC

Carboplatin AUC = 6 every 3 weeks for eight cycles + docetaxel 75 mg/m2 weekly every 3 weeks for eight cycles + trastuzumab 4 mg/kg loading dose, then 2 mg/kg on days 1,8, and 15 every 3 weeks for eight cycles, then 6 mg/kg every 3 weeks until PD

Docetaxel 100 mg/m2 on every 3 weeks for eight cycles + trastuzumab 4 mg/kg loading dose, then 2 mg/kg on days 1,8, and 15 every 3 weeks for eight cycles, then 6 mg/kg every 3 weeks until PD

TTP

132

131

37.4

37.1

p = 0.99

10.4

11.1

0.914 (0.694, 1.203), p = 0.57

NCT00294996

Baselga et al. [14]

2014

Women with HER2-overexpressing mBC and no prior chemotherapy for metastatic disease

NPLD (50 mg/m2 every 3 weeks for six cycles) + trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) + paclitaxel (80 mg/m2 weekly)

Trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly) + paclitaxel (80 mg/m2 weekly)

PFS

181

182

33.6

28.9

0.79 (0.61, 1.03), p = 0.083

16.1

14.5

0.84 (0.65, 1.08), p = 0.174

CLEOPATRA study

Baselga et al. [13]; Swain et al. [2]; Swain et al. [21]

2013

Women (≥18 years old) with HER2-positive mBC (measurable disease or nonmeasurable disease); LEVF ≥ 50 %; ECOG-PS 0–1. Previous chemotherapy or biological treatment for metastatic disease was not allowed

Pertuzumab 840 mg loading dose, then 420 mg every 3 weeks until PD + trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks until PD + docetaxel 75 mg/m2 every 3 weeks for six cycles

Placebo 840 mg loading dose, then 420 mg every 3 weeks until PD + trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks until PD + docetaxel 75 mg/m2 every 3 weeks for six cycles

PFS

402

406

56.5

40.8

0.68 (0.56, 0.84), p < 0.001

18.7

12.4

0.68 (0.58, 0.80), p = 0.001

BOLERO-1

Hurwitz et al. [32]

2015

Women (≥18 years old) with locally assessed HER2-positive, locally recurrent invasive breast cancer unamenable to resection with curative intent or metastatic disease, with ECOG-PS 0–1, with measurable disease as per RECIST or bone lesions in the absence of measurable disease; no previous systemic therapy for advanced disease was allowed

Everolimus (10 mg/day) + trastuzumab (4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle) + paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 4-week cycle)

Placebo + trastuzumab (4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle) + paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 4-week cycle)

PFS^a

480

239

NA

NA

NA

14.95

14.49

0.89 (0.73, 1.08), p = 0.1166