A Study of Onartuzumab (MetMAb) in Combination With Bevacizumab (Avastin) Plus Platinum And Paclitaxel or With Pemetrexed Plus Platinum in Patients With Non-Squamous Non-Small Cell Lung Cancer

• Progression-free survival (tumor assessments according to RECIST criteria) [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]
• Progression-free survival: Subgroup of patients with Met diagnostic positive tumors [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]

• Overall survival [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]
• Overall response rate (tumor assessments according to RECIST criteria) [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]
• Duration of response (time from first documented objective response to disease progression) [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]
• Disease control rate (rate of partial response plus complete response plus stable disease for at least 6 weeks) [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]
• Safety: Incidence of adverse events [ Time Frame: up to approximately 23 months ] [ Designated as safety issue: No ]
• Pharmacokinetics: serum concentration (Cmin/Cmax) [ Time Frame: Pre- and post-dose on Day 1 of Cycles 1, 2 and 4 and at study termination ] [ Designated as safety issue: No ]
• Serum concentrations of bevacizumab/paclitaxel/pemetrexed/platinum in combination with MetMAb [ Time Frame: Pre- and post-dose on Day 1 of Cycles 1 and 4 ] [ Designated as safety issue: No ]
• Serum levels of anti-therapeutic antibodies (MetMAb ATAs) [ Time Frame: Pre-dose Day 1 of Cycles 1, 2 and 4 ] [ Designated as safety issue: No ]

This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of RO5490258 (MetMab) in combination with either of two backbone chemotherapy regimens in the first-line setting in patients with incurable Stage IIIB or IV non-squamous non-small cell lung cancer. In Cohort 1, patients will be randomized to receive 4 cycles of bevacizumab (Avastin) 15 mg/kg iv, paclitaxel 200 mg/m2 iv, platinum (cisplatin/carboplatin) iv plus either MetMab 15 mg/kg iv or placebo on Day 1 of each 21-day cycle. In Cohort 2, patients will be randomized to receive pemetrexed 500 mg/m2 iv, platinum (cisplatin/carboplatin) iv plus either MetMAb 15 mg/m2 iv or placebo on Day 1 of each 21-day cycle. Patients who have not progressed after 4 cycles will be offered maintenance therapy with their assigned treatment of bevacizumab plus either MetMAb or placebo (Cohort 1) or pemetrexed plus either MetMAb or placebo (Cohort 2). Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

• Drug: RO5490258
  15 mg/kg iv, Day 1 of each 21-day cycle
  Other Name: MetMAb
• Drug: bevacizumab [Avastin]
  15 mg/kg iv, Day 1 of each 21-day cycle
• Drug: pemetrexed
  500 mg/m2, Day 1 of each 21-day cycle
• Drug: Placebo
  Matching RO5490258 (MetMAb) placebo iv, Day 1 of each 21-day cycle
• Drug: cisplatin/carboplatin
  standard dose iv, Day 1 of each 21-day cycle, 4 cycles
• Drug: paclitaxel
  200 mg/m2 iv, Day 1 of each 21-day cycle, 4 cycles

• Experimental: Bevacizumab+MetMAb
  Interventions:

  • Drug: RO5490258
  • Drug: bevacizumab [Avastin]
  • Drug: cisplatin/carboplatin
  • Drug: paclitaxel
• Active Comparator: Bevacizumab+Placebo
  Interventions:

  • Drug: bevacizumab [Avastin]
  • Drug: Placebo
  • Drug: cisplatin/carboplatin
  • Drug: paclitaxel
• Experimental: Pemetrexed+MetMAb
  Interventions:

  • Drug: RO5490258
  • Drug: pemetrexed
  • Drug: cisplatin/carboplatin
• Active Comparator: Pemetrexed+Placebo
  Interventions:

  • Drug: pemetrexed
  • Drug: Placebo
  • Drug: cisplatin/carboplatin

Inclusion Criteria:

• Adult patients, >/= 18 years of age
• Histologically or cytologically confirmed Stage IIIB or Stage IV non-squamous non-small cell lung cancer (NSCLC)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• For patients who received prior adjuvant chemotherapy: a treatment-free interval of at least 12 months since last chemotherapy cycle
• Adequate tissue for central IHC assay of Met receptor, and EGFR testing if EGFR status is unknown
• Radiographic evidence of disease

Exclusion Criteria:

• Prior systemic treatment for Stage IIIB or IV non-squamous NSCLC
• Evidence of mixed NSCLC with a predominance of the squamous cell type
• Prior exposure to experimental treatment targeting either the HGF or Met pathway
• Patients with tumors confirmed to have EGFR-activating mutations who are suitable for anti-EGFR therapy (e.g. gefitinib or erlotinib), as determined by the investigator
• Known central nervous system (CNS) disease, other than stable, treated brain metastases
• History of another malignancy in the previous 3 years, except for history of in situ cancer or basal or squamous cell skin cancer
• Uncontrolled diabetes
• Pregnant or lactating women
• Impaired bone marrow, liver or renal function (as defined by protocol)
• Significant history of cardiovascular disease
• Positive for HIV infection