. Author manuscript; available in PMC: 2013 Nov 10.

Published in final edited form as: Cancer Treat Rev. 2011 Feb 10;37(7):10.1016/j.ctrv.2011.01.002. doi: 10.1016/j.ctrv.2011.01.002

Table 2.

TTP/PFS and survival data from randomized trials of targeted biological agents in advanced breast cancer.

Drugs	Patients	Treatment	Primary endpoint(s)study design	Median TTP/PFS	Median OS
Paclitaxel (P) ± bevacizumab (B). (E2100; Miller et al., 2007; O’Shaughnessy et al. 2009^9,23)	Patients with MBC treated first line (patients with HER2-positive MBC were eligible only if they had received trastuzumab) (N = 722). No prior therapies for MBC	BP: bevacizumab 10 mg/kg on days 1 and 15 + paclitaxel 90 mg/m² on days 1, 8, and 15 every 4 weeks (n = 368) or P: paclitaxel 90 mg/m² on days 1, 8, and 15 every 4 weeks (n = 354)	Primary endpoint: PFS. No crossover	BP vs. P: PFS 11.8 vs. 5.9 months; HR =.0.60 (P < 0.001). In triple-negative breast cancer: 10.2 vs. 4.7 months; HR = 0.45. In ER+/PR + breast cancer: PFS 14.4 vs. 8.0 months; HR = 0.54	BP vs. P: 26.7 vs. 25.2 months; HR = 0.88 (P = 0.16)
Docetaxel (D) ± bevacizumab (B). (AVADO; Miles et al., 2008; 2009; O’Shaughnessy et al., 2009^23-25)	Patients with HER2-negative locally advanced or MBC treated first-line (N = 736). No prior therapies for MBC	Docetaxel 100 mg/m² every 3 weeks (n = 241) ± bevacizumab 7.5 mg/kg (n = 248) or 15 mg/kg (n = 247) every 3 weeks	Primary endpoint: PFS. No crossover; however, 90 patients in the placebo arm received B on progression	D + placebo vs. DB7.5 vs. DB15: PFS 8.1 vs. 9.0 vs. 10.0 months. D + placebo vs. DB7.5: HR = 0.80 (P = 0.0450). D + placebo vs. DB15: HR = 0.67 (P = 0.0002). In triple-negative breast cancer (D + placebo vs. DB15): PFS 8.1 vs. 6.0 months; HR = 0.60	D + placebo vs. DB7.5 vs. DB15: 31.9 vs. 30.8 vs. 30.2 months. D + placebo vs. DB7.5: HR = 1.05 (P = 0.7198). D + placebo vs. DB15: HR = 1.03 (P = 0.8528)
Bevacizumab (B) + chemotherapy (capecitabine [X], taxane [T], or anthracycline [A]) vs. placebo + chemotherapy. (RIBBON-1; Robert et al., 2009²⁶)	Patients with HER2-negative LABC or MBC (N = 1237). No prior therapies for MBC	B or placebo: 15 mg/kg every 3 weeks (BX: n = 206, placebo + X: n = 409, BAT: n = 415, placebo + AT: n = 207) + chemotherapy (capecitabine [X]: 2000 mg/m² × 14 days, nab-paclitaxel: 260 mg/m², or docetaxel: 75 or 100 mg/m² every 3 weeks or anthracycline-based chemotherapy every 3 weeks)	Primary endpoint: PFS. No crossover; however, 60% of patients in the placebo arm and 50% of patients in the B arm received B on progression	BX vs. placebo X: PFS 8.6 vs. 5.7 months; HR = 0.688 (95% CI: 0.564–0.840; P = 0.0002). BAT vs. placebo + AT: PFS 9.2 vs. 8.0 months; HR = 0.644 (95% CI: 0.522–0.795; P < 0.0001). In triple-negative breast cancer. BX vs. placebo X: PFS 6.1 vs. 4.2 months; HR = 0.72. BAT vs. placebo + AT: 14.5 vs. 8.2 months HR = 0.78	BX vs. placebo X: 29.0 vs. 21.2 months HR = 0.847 (95% CI: 0.631–1.138; P = 0.2706). BAT vs. placebo + AT: 25.2 vs. 23.8 months; HR = 1.032 (95% CI: 0.774–1.376; P = 0.8298)
Bevacizumab + chemotherapy or placebo + chemotherapy (RIBBON-2; Brufsky et al., 2009; 2010^27,28)	Patients with HER2-negative MBC treated second line (N = 684). Prior therapies for MBC: 1	Bevacizumab (B) or placebo: 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, depending on the chemotherapy regimen (chemotherapy + B: n = 225, chemotherapy + placebo: n = 459) + chemotherapy (paclitaxel [P]: 90 mg/m²/week for 3 of the 4 weeks, P: 175 mg/m² every 3 weeks, nab-paclitaxel [nabP]: 260 mg/m² every 3 weeks, docetaxel [D]: 75–100 mg/m² every 3 weeks, gemcitabine [G]: 1250 mg/m² on days 1 and 8 every 3 weeks, capecitabine [X]: 2000 mg/m² days 1–14 every 3 weeks, or vinorelbine [V] 30 mg/m²/week	Primary endpoint: PFS. No crossover	Chemotherapy + B vs. chemotherapy + placebo: PFS 7.2 vs. 5.1 months; HR = 0.775 (P = 0.0072). In triple-negative breast cancer: PFS 6.0 vs. 2.7 months; HR = 0.49. In ER+/PR + breast cancer: PFS 7.4 vs. 6.0 months; HR = 0.89	Chemotherapy + B vs. chemotherapy + placebo: 18.0 vs. 16.4 months (P = 0.372)
Chemotherapy ± trastuzumab (H). (Slamon et al., 2001³⁷)	Women with HER2-positive MBC treated first line (N = 469). No prior therapies for MBC	Chemotherapy (doxorubicin: 60 mg/m² or epirubicin: 75 mg/m² + cyclophosphamide: 600 mg/m² for patients who had never before received an anthracycline; or paclitaxel: 175 mg/m² for patients who had received adjuvant) once every 3 weeks for 6 cycles (n = 234) ± H: trastuzumab 4 mg/kg followed by 2 mg/kg once a week until disease progression (n = 255)	Primary endpoint: TTP. Two thirds of patients in the chemotherapy alone arm received trastuzumab after disease progression	Chemotherapy + H vs. chemotherapy alone: TTP 7.4 vs. 4.6 months; HR = 0.52 (95% CI: 0.41–0.63; P < 0.001)	Chemotherapy + H vs. chemotherapy alone: 25.1 vs. 20.3 months; HR = 0.80 (95% CI: 0.64–1.00; P = 0.046)
Docetaxel (D) ± trastuzumab (H). (Marty et al., 2005³⁸)	Women with HER2-positive MBC treated first line (N = 186). No prior therapies for MBC	HD: docetaxel 100 mg/m² every 3 weeks for 6 cycles + trastuzumab 4 mg/kg followed by 2 mg/kg weekly until disease progression (n = 92) or D: 100 mg/m² every 3 weeks for 6 cycles (n = 94)	Primary endpoint: ORR. 57% of patients in the docetaxel-alone arm crossed over to receive trastuzumab after disease progression or due to toxicity or other reasons	HD vs. D: TTP 11.7 vs. 6.1 months (P = 0.0001)	HD vs. D: 31.2 vs. 22.7 months (P = 0.0325)
Capecitabine (X) ± trastuzumab (H). (von Minckwitz et al. 2008³⁹)	Women with HER2-positive, LABC or MBC that progressed during treatment with trastuzumab ± adjuvant and/or 1st-line metastatic chemotherapy (N = 156). Prior therapies for MBC: 0 or 1	XH: capecitabine 2500 mg/m² on days 1–14, every 21 days + trastuzumab 6 mg/kg, every 3 weeks (n = 78) or X: capecitabine 2500 mg/m² on days 1–14, every 21 days (n = 78)	Primary endpoint: TTP. No crossover	XH vs. X: TTP: 8.2 vs. 5.6 months; HR = 0.69 (P = 0.026)	XH vs. X: 25.5 vs. 20.4 months; HR = 0.76 (P = 0.26)
Capecitabine (X) ± lapatinib (L). (Cameron et al., 2008⁴⁰)	Patients with advanced or metastatic HER2-positive breast cancer with prior therapy including an anthracycline, a taxane and trastuzumab (N = 399). Any number of prior therapies for MBC permitted	LX: lapatinib 1250 mg/day continuously + capecitabine 2000 mg/m² on days 1–14 of a 21-day cycle (n = 82) or X: capecitabine 2500 mg/m² on days 1–14 of a 21-day cycle (n = 102)	Primary endpoint: TTP. Crossover from X to LX allowed at study completion	LX vs. X. TTP 6.2 vs. 4.3 months, HR = 0.57 (95% CI: 0.43–0.77; P < 0.001)	LX vs. X. 15.6 vs. 15.3; HR = 0.78 (95% CI: 0.55–1.12; P = 0.177)
Lapatinib (L) ± trastuzumab (H). (O’Shaughnessy et al. 2008; Blackwell et al., 2009^41,42)	Women with heavily pretreated (prior anthracyclines and taxanes) HER2-positive MBC progressing on H (N = 296). Any number of prior therapies for MBC permitted	LH: lapatinib 1000 mg/day + trastuzumab 4 mg/kg followed by 2 mg/kg weekly (n = 148) or L: lapatinib 1500 mg/day (n = 148)	Primary endpoint: PFS. 52% of patients in the L arm crossed over to LH after disease progression	LH vs. L: PFS 12.0 vs. 8.4 months, HR = 0.77 (95% CI: 0.6–1.0; P = 0.029)	LH vs. L: 60.7 vs. 41.4 months, HR = 0.74 (95% CI: 0.57–0.97; P = 0.026)
Gemcitabine + carboplatin (GC) ± BSI-201. (O’Shaughnessy et al., 2008⁴¹)	Patients with pre-treated triple-negative MBC who had received received ≤ 2 prior cytotoxic regimens (N = 86; planned N = 120). Any number of prior therapies for MBC permitted	GC: gemcitabine 1000 mg/m² and carboplatin AUC = 2 on days 1 and 8 (n = 57) ± BSI-201: 5.6 mg/kg on days 1, 4, 8, and 11 every 21 days (n = 59)	Primary endpoint: Clinical benefit rate. No crossover	GC + BSI-201 vs. GC: PFS 6.9 vs. 3.3 months; HR = 0.34 (95% CI: 0.20–0.58; P < 0.0001)	GC + BSI-201 vs. GC: 9.2 vs. 5.7 months; HR = 0.35 (95% CI: 0.19–0.65; P = 0.0005)