Table 2: Randomized combination cytotoxic plus targeted or biologic therapy for patients with MBC.

Therapeutic combinationApproval statusClinical dataMost common grade 3-4 adverse events

Trastuzumab plus chemotherapy (doxorubicin or epirubicin plus cyclophosphamide or paclitaxel) (TC) [25]Phase III
Approved
TC versus C alone  
ORR: 50% versus 32% (P < 0.001)
TTP: median 7.4 versus 4.6 months (P < 0.001)
TTF: median 6.9 versus 4.5 months (P < 0.001)
DR: median 9.1 versus 6.1 months (P < 0.001)
Death rate at 1 year: 22% versus 33% (P = 0.008)
OS: median 25.1 versus 20.3 months (P = 0.046)
TC versus C alone*  
Leukopenia: 11% versus 9%
Asthenia: 7% versus 7%
Fever: 8% versus 4%
Pain: 6% versus 7%
Heart failure: 10% versus 2%
Nausea: 5% versus 7%
Vomiting: 5% versus 7%
Alopecia: 26% versus 35%

Capecitabine plus bevacizumab (XB) [74]Phase III
Not approved in the United States; approved in the European Union
XB versus single-agent X 
ORR: 19.8 versus 9.1% (P = 0.001)
PFS: median 4.86 versus 4.17 months, HR = 0.98 (P = 0.857)
OS: median 15.1 months versus 14.5 months (NS)
XB versus single-agent X  
Diarrhea: 11.8% versus 10.7%
Hand-foot syndrome: 27.5% versus 24.2%
Hypertension: 17.9% versus 0.5%
Thrombotic event: 5.6% versus 3.7%

Paclitaxel plus bevacizumab (PB) [26]Phase III
Not approved in the United States; approved in the European Union
PB versus single-agent P  
ORR: 36.9 versus 21.2% (P < 0.001)
PFS: median 11.8 versus 5.9 months, HR = 0.60
(P < 0.001)
OS: median 26.7 versus 25.2 months, HR = 0.88 (P = 0.02)
PB versus single-agent P  
Infection: 9.3% versus 2.9%
Fatigue: 9.1% versus 4.9%
Sensory neuropathy: 23.5% versus 17.7%
Hypertension: 14.8% versus 0%

Capecitabine plus lapatinib (XL) [75, 76]Phase III
Approved
XL versus single-agent X  
ORR: 22% versus 14% (P = 0.09)
TTP: median 8.4 versus 4.4 months, HR =0.57 (95% CI: 0.43–0.77; P < 0.001)
OS: HR = 0.78 (95% CI: 0.55–1.12; P = 0.177)
XL versus single-agent X [75]   
Diarrhea: 14% versus 10%
Hand-foot syndrome: 12% versus 14%

Lapatinib plus trastuzumab (LT) [7779]Phase III
Not approved
LT versus single-agent L  
ORR: 10.3% versus 6.9% (P = 0.46)
PFS: median 12.0 versus 8.4 weeks, HR = 0.77 (95% CI: 0.6–1.0; P = 0.029)
OS: median 60.7 versus 41.4 weeks, HR = 0.74 (95% CI: 0.57–0.97; P = 0.026)
LT versus single-agent L [79]   
Diarrhea: 7% versus 7%

CI: confidence interval; DR: duration of response; HR: hazard ratio; NS: not significant; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; TTF: time to treatment failure; TTP: time to progression.
*Percentage with severe event.