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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

From: The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer – a systematic review

Clinical trial Reference Year Target population T1 T2 Primary endpoint of efficacy Patients on T1, n Patients on T2, n OS T1 OS T2 HR (95 % CI), p value PFS T1 PFS T2 HR (95 % CI), p value
Chemotherapy ± trastuzumab or lapatinib
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
Chemotherapy + trastuzumab or chemotherapy + lapatinib
CEREBELa 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
Lapatinib + trastuzumab
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
Trastuzumab emtansine (T-DM1)
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
Everolimus in trastuzumab-resistant patients
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
  1. CI confidence interval, CNS central nervous system, ECOG-PS Eastern Cooperative Oncology Group performance status, HER2 human epidermal growth factor receptor 2, HR hazard ratio, LVEF left ventricular ejection fraction mBC metastatic breast cancer, NA not available, NYR not yet reached, OS overall survival, PD progression of disease, PFS progression-free survival, T1 treatment 1, T2 treatment 2, T-DM1 trastuzumab emtansine,TTP time to progression
  2. aCEREBEL was included in the list of studies assessing second-line or beyond therapies because patients were required to have received prior chemotherapy for (neo)adjuvant or metastatic disease, according to the inclusion criteria of the study. However, it should be noted that nearly 43 % of patients in the lapatinib plus capecitabine arm (117 of 271 patients) and 45 % of patients in the trastuzumab plus capecitabine arm (121 of 269 patients) had not received prior treatment for the metastatic disease