A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-Positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-Directed Therapy (TH3RESA)

• Progression-free survival by investigator assessment according to RECIST [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]

• Objective response rate by independent review, tumor assessments according to RECIST criteria [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]

• Objective response rate [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Duration of objective response (DOR) [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Land mark survival rate (6 months/1 year) [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Safety: Incidence of adverse events [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Time to pain symptom progression as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire BM22 [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Global Health Status/Quality of Life as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Global Health Status as measured by Euro-Qol 5D [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Pharmacokinetics: serum concentration of trastuzumab emtansine [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Pharmacokinetics: plasma concentration of DM1 [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]

• Progression-free survival (PFS) [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Duration of objective response (DOR) [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Clinical benefit rate, defined as proportion of patients achieving an objective response or stable disease for at least 6 months from randomization [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Land mark survival rate (6 months/1 year) [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]
• Safety: Incidence of adverse events [ Time Frame: approximately 3.5 years ] [ Designated as safety issue: No ]

This randomized, multicenter, two-arm, open-label study (TH3RESA) will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) in comparison with treatment of the physician's choice in patients with metastatic or unresectable locally advanced/recurrent HER2-positive breast cancer. Eligible patients will be randomized to receive either T-DM1 3.6 mg/kg intravenously every 21 days or treatment of the physician's choice. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs. This study is also known under Roche study protocol number BO25734.

• Drug: trastuzumab emtansine [Kadcyla]
  3.6 mg/ kg intravenously every 21 days
• Drug: anti-cancer therapy
  Treatment of physician's choice (chemotherapy, hormonal therapy, biologic drug and/or HER2-directed therapy)

• Experimental: A
  Intervention: Drug: trastuzumab emtansine [Kadcyla]
• Active Comparator: B
  Drug: anti-cancer therapy
  Intervention: Drug: anti-cancer therapy

Inclusion Criteria:

• Adult patients, >/= 18 years of age
• Histologically or cytologically documented breast cancer
• Metastatic or unresectable locally advanced/recurrent breast cancer
• HER2-positive disease by prospective laboratory confirmation
• Disease progression on the last regimen received as defined by the investigator
• Prior treatment with an trastuzumab, a taxane, and lapatinib
• Disease progression after at least two regimens of HER2-directed therapy in the metastatic or unresectable locally advanced/recurrent setting
• Adequate organ function, as evidenced by laboratory results
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• LVEF >/= 50% by ECHO or MUGA

Exclusion Criteria:

• Chemotherapy </= 21 days before first study treatment
• Trastuzumab </= 21 days before first study treatment
• Lapatinib </= 14 days before first study treatment
• Prior enrolment in a T-DM1 containing study, regardless whether the patient received prior T-DM1
• Brain metastases that are untreated or symptomatic, or require any radiation, surgery or corticosteroid therapy to control symptoms within 1 month of randomization