Table 2 Summary of design and results of studies assessing second-line or beyond therapies for the treatment of patients diagnosed with HER2-positive metastatic breast cancer

Geyer 2006

Geyer et al. [26]; Cameron et al. [3]; Cameron et al. [25]

2006

Women with progressive, HER2-positive, locally advanced or metastatic breast cancer who had previously been treated with a minimum of an anthracycline, a taxane and trastuzumab

Lapatinib 1250 mg daily + capecitabine at a dose of 2000 mg/m2 in two divided doses on days 1 through 14 of a 21-day cycle

Capecitabine 2500 mg/m2 in two divided doses on days 1 through 14 of a 21-day cycle

TTP

198

201

15.6

15.3

0.78 (0.55, 1.12) p = 0.177

8.4

4.1

0.47 (0.33, 0.67), p < 0.001

A German Breast Group 26/Breast International Group 03–05 study

von Minckwitz et al. [29]; von Minckwitz et al. [30]

2009

Women with pathologically confirmed, HER-2–positive, locally advanced or metastatic breast cancer

Capecitabine 2500 mg/m2 (1250 mg/m2 twice daily) on days 1 through 14 followed by 1 week of rest

Capecitabine 2500 mg/m2 (1250 mg/m2 twice daily) on days 1 through 14 followed by 1 week of rest + trastuzumab 6 mg/kg body weight as a 30-minute infusion every 3 weeks until PD

TTP

78

78

20.6

24.9

0.76 (0.48, 1.22) p = 0.257

5.6

8.2

0.69 (0.48, 0.97), p = 0.034

CEREBEL^a

Pivot et al. [28]

2015

Women with HER2-positive mBC and without baseline CNS metastases. Patients were required to have received prior anthracycline and/or taxanes for (neo)adjuvant or metastatic disease. Prior trastuzumab was allowed but not required

Trastuzumab infusion of 6 mg/kg every 3 weeks (with possibly a loading dose of 8 mg/kg on day 1) and capecitabine 2500 mg/m2 per day on days 1 through 14, every 21 days

Lapatinib 1250 mg once daily and capecitabine 2000 mg/m2 per day on days 1 through 14, every 21 days

Incidence of CNS metastases as first site of relapse

269

271

27.3

22.7

1.34 (0.95, 1.64), p = 0.095

8.1

6.6

1.30 (1.04, 1.64), p = 0.021

EGF104900 study

Blackwell et al. [24]; Blackwell et al. [5]

2012

Women with ErbB2-positive mBC who experienced progression on prior trastuzumab-containing regimens

Lapatinib 1000 mg daily in combination with intravenous trastuzumab 2 mg/kg weekly (after the initial 4 mg/kg loading dose)

Lapatinib 1500 mg daily

PFS

148

148

12.04

9.1

0.75 (0.53, 1.07) p = 0.106

2.8

1.9

0.73 (0.57, 0.93), p = 0.008

EMILIA

Verma et al. [4]

2012

HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

T-DM1 3.6 mg/kg every 3 weeks until PD

Lapatinib 1250 mg/day + capecitabine 1000 mg/m2 twice a day on days 1–14 for 3 weeks until PD

PFS, OS

495

496

30.9

25.1

0.68 (0.55, 0.85) p < 0.001

9.6

6.4

0.65 (0.55, 0.77), p < 0.001

TH3RESA

Krop et al. [27]

2014

Women (≥18 years, LVEF ≥ 50 %, ECOG-PS 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting

Trastuzumab emtansine (3.6 mg/kg intravenously every 21 days)

Physician’s choice

PFS, OS

404

198

NYR

14.9

0.552 (0.369, 0.826), p = 0.0034

6.2

3.3

0.528 (0.422, 0.661), p < 0.0001

BOLERO-3

André et al. [23]

2014

Women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy

Daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m(2))

Placebo plus trastuzumab plus vinorelbine, in 3-week cycles

PFS

284

285

NA

NA

NA

7.00

5.78

0.78 (0.65, 0.95), p = 0.0067