A Study in Non-Small Cell Lung Cancer

Inclusion Criteria:

* The participant has histologically or cytologically confirmed, nonsquamous (adenocarcinoma/large cell or other) NSCLC.
* The participant has Stage IV disease at the time of study entry.
* Participants with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 14 days prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The participant may have no evidence of Grade 1 (or greater) Central Nervous System (CNS) hemorrhage based on pretreatment scans(performed within 21 days before randomization).
* The participant has measurable or nonmeasurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 guidelines.
* The participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
* If prior adjuvant or neoadjuvant chemotherapy, the last dose of adjuvant or neoadjuvant treatment was administered at least 6 months prior to randomization.
* The participant has adequate bone marrow reserve, and renal and hepatic function
* The participant has fasting serum glucose less than or equal to 125 mg/dL, and hemoglobin A1C less than or equal to 6%.
* Females with reproductive potential: Must have a negative serum or urine pregnancy test within 7 days prior to the first dose of any study drug.
* Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for 6 months following the last dose of any study drug.
* The participant has the ability to understand and the willingness to sign a written informed consent form.
* Previous radiation therapy is allowed to less than 25% of the bone marrow, but should have been limited and must not have included whole pelvis radiation.
* The participant has archived tumor tissue available for analysis (can be either primary tumor or metastases).
* The participant has an estimated life expectancy of at least 12 weeks.

Exclusion Criteria:

* Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
* Participants who have squamous histology.
* The participant's tumor fully or partially contains Small Cell Lung Cancer (SCLC).
* The participant has leptomeningeal disease.
* The participant is currently or has previously received chemotherapy for advanced (Stage IV) NSCLC.
* The participant has a history of treatment with other agents targeting the Insulin-like or Epidermal Growth factor receptors.
* Participants who have received prior Pemetrexed treatment.
* The patient has a known allergy/history of hypersensitivity reaction to any of the treatment components.
* The participant has diabetes mellitus as defined by being treated with glucose lowering medications in the past 3 months prior to enrollment.
* The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia,or psychiatric/social situations that would limit compliance with study requirements.
* The participant has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy.
* The participant has undergone major surgery within 28 days prior to randomization.
* The participant has received a prior autologous or allogeneic organ or tissue transplantation.
* The participant is pregnant or lactating.
* The participant has a history of another primary cancer, with the exception of the following: curatively resected nonmelanomatous skin cancer, curatively treated carcinoma in situ, or other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 5 years.
* The participant has superior vena cava syndrome contraindicating hydration.
* The participant has current clinically-relevant coronary artery disease (New York Heart Association III or IV) or uncontrolled congestive heart failure.
* The participant has any Grade 2 (or greater) peripheral neuropathy.
* The participant has clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry.
* The participant is unable to interrupt aspirin or other nonsteroidal anti-inflammatory agents, other than an aspirin dose less than or equal to 1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
* The participant is unwilling or unable to take premedications (folic acid, vitamin B12, or corticosteroids) required by the pemetrexed label.
* The participant has received a recent (within 30 days of enrollment) or is receiving concurrent yellow fever vaccination.