Inclusion Criteria:

1. Histologic or cytologic diagnosis of advanced NSCLC, excluding squamous cell and
small cell histology. Tumors with mixed NSCLC histologies are eligible, as long as
the predominant histology is not squamous. If small-cell elements are present or not
otherwise specified histologically, the patient is not eligible.

2. Recurrent or Stage IV disease (according to American Joint Committee on Cancer (AJCC)
staging system, v7.0).

3. No prior systemic chemotherapy, immunotherapy, targeted therapy, or biological
therapy; adjuvant therapy is allowed as long as the interval from end of adjuvant
therapy until disease progression was >12 months.

4. No prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow
area. Radiation therapy must be completed at least 2 weeks prior to randomization.
Must have recovered from acute adverse effects prior to randomization.

5. At least one measurable lesion according to Response Evaluation Criteria in Solid
Tumors (RECIST) v1.1.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.

7. Baseline laboratory values as follows:

- Absolute neutrophil count (ANC) ≥1500/μL

- Hemoglobin (Hgb) ≥10 g/dL

- Platelets ≥100,000/μL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ≤3.0 x the
upper limit of normal (ULN); 5 x ULN if known hepatic metastases.

- Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert's disease

- Serum creatinine ≤1.5 x ULN. If creatinine is >1.5, calculate creatinine
clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method:

Glomular Filtration Rate (GFR) = (140-age) x (weight/kg) x (0.85 if female) (72 x
serum creatinine mg/dL)

8. Fertile male patients willing to use adequate contraceptive measures.

9. Female patients who are not of child-bearing potential, and fertile female patients
of child-bearing potential who agree to use adequate contraceptive measures, who are
not breastfeeding, and who have a negative serum or urine pregnancy test within 72
hours prior to start of randomization.

10. Life expectancy ≥ 12 weeks.

11. Must be ≥18 years of age at the time of consent.

12. Willingness and ability to comply with trial and follow-up procedures.

13. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Known anaplastic lymphoma kinase (ALK) translocation and epidermal growth factor
receptor (EGFR) "activating" mutations where first-line treatment with targeted
tyrosine kinase inhibitor therapy is more appropriate.

2. Known central nervous system (CNS) disease other than neurologically stable, treated
brain metastases - defined as metastasis having no evidence of progression or
hemorrhage after treatment and no ongoing requirements for corticosteroids, (e.g.,
dexamethasone) for at least 2 weeks.

3. Any of the following cardiac diseases currently or within the last 6 months as
defined by New York Heart Association (NYHA) ≥ Class 2:

- Unstable angina pectoris

- Congestive heart failure

- Acute myocardial infarction

- Conduction abnormality not controlled with pacemaker or medication

- Significant ventricular or supraventricular arrhythmias (Patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac
abnormalities are eligible).

4. Patients currently receiving therapeutic anticoagulation.

5. Pregnant or lactating women.

6. Any serious, active underlying medical condition that would impair the ability of the
patient to receive study treatment, such as diabetes mellitus or infection.

7. Unable or unwilling to take folic acid or vitamin B12.

8. Active second malignancy (except non-melanomatous skin or superficial bladder cancer)
defined as requiring current need for cancer therapy or at high risk of recurrence
(>350%) during the study.

9. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

10. Inability or unwillingness to comply with trial and/or follow-up procedures outlined
in the protocol.