A randomized, double-blind, 3-arm (1:1:1) study in subjects with first-line Stage IV non-squamous NSCLC. The purpose is to test the efficacy and safety of demcizumab, when given in combination with carboplatin and pemetrexed compared to placebo. The administration of carboplatin and pemetrexed is a standard treatment for patients with non-squamous non-small cell lung cancer.

Patients will be enrolled at centers in North America, Western Europe, Australia and New Zealand. Up to 28 days (4 weeks) prior to treatment.

If enrolled in the study, you will receive intravenous (in the vein) infusions of demcizumab (or placebo), carboplatin, and pemetrexed administered on the same day, every 21 days for 4 cycles, or until it has been shown that your cancer has gotten worse. If your physician decides to delay treatment with one of the agents due to side effects, the other agents may still be administered as scheduled. After 4 cycles, if you have stable or improved disease, you will continue to receive pemetrexed once every 21 days as maintenance therapy. After 8 cycles, if you have stable or improved disease, you may receive demcizumab (or placebo), every 21 days for 4 more cycles.

You will undergo assessments every 6 weeks to determine the status of your disease.

Main Inclusion Criteria:

1. Signed Informed Consent Form
2. Histologically or cytologically confirmed Stage IV non-squamous NSCLC
3. Availability of FFPE (formalin-fixed paraffin-embedded) tumor tissue, either fresh core-needle-biopsied or archived
4. Age > or = to 21 years
5. ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1
6. Disease that is measurable per RECIST v1.1
7. Adequate organ and marrow function
8. For women of childbearing potential, agreement to use two effective forms of contraception

Main Exclusion Criteria:

1. Histologically or cytologically documented, advanced, mixed non-small cell and small cell tumors or mixed adenosquamous carcinomas
2. NSCLC with known EGFR (epidermal growth factor receptor ) mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4 [echinoderm microtubule-associated protein-like 4]-ALK [anaplastic lymphoma kinase])
3. Prior or ongoing therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy, or investigational therapy) for the treatment of Stage IV non-squamous NSCLC
4. Evidence of tumor invading major blood vessels, cavitation of one or more pulmonary tumor mass(es) or tracheo-esophageal fistula
5. Brain metastases, leptomeningeal disease, uncontrolled seizure disorder, or active neurologic disease
6. Malignancies other than non-squamous NSCLC successfully treated within 3 years prior to randomization (with the exception of certain early-stage cancers)
7. History of a significant allergic reaction attributed to humanized or human monoclonal antibody therapy
8. Significant intercurrent illness defined as an illness that may result in the subject's death prior to their death from non-squamous NSCLC and/or significantly limit their ability to comply with the requirements of this study
9. Recent hemoptysis >2.5 mL or serious bleeding from another site, known bleeding disorder or coagulopathy or therapeutic anti-coagulation
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization, or anticipation of need for major surgical procedure during the course of the study