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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

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
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
Chemotherapy + lapatinib versus chemotherapy + trastuzumab
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
Hormone therapy ± trastuzumab or lapatinib
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
Chemotherapy A + trastuzumab versus chemotherapy B + trastuzumab
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
Chemotherapy + trastuzumab and pertuzumab
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
Everolimus in trastuzumab-resistant patients
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) PFSa 480 239 NA NA NA 14.95 14.49 0.89 (0.73, 1.08), p = 0.1166
  1. AUC area under the curve, CI confidence interval, ECOG-PS Eastern Cooperative Oncology Group performance status, ER estrogen receptor, HER2 human epidermal growth factor receptor 2, HR hazard ratio, LACB locally advanced breast cancer, LVEF left ventricular ejection fraction, mBC metastatic breast cancer, NA not available, NPLD nonpegylated liposomal doxorubicin, ORR overall response rate, OS overall survival, PD progression of disease, PFS progression-free survival, PgR progesterone receptor, RECIST Response Evaluation Criteria In Solid Tumors, T1 treatment 1, T2 treatment 2, TTP time to progression
  2. aResults for the full population, irrespective of the hormone receptor status