Inclusion Criteria:

• Men and women ≥ 18 years of age.
• Histologically or cytologically confirmed stage IIIB or IV NSCLC with non-squamous histology
• Recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance
• Neoadjuvant/adjuvant cytotoxic chemotherapy initiated < 12 months prior to study randomization will be counted as one prior treatment
• Neoadjuvant/adjuvant cytotoxic chemotherapy initiated ≥ 12 months prior to study randomization will not be counted as one prior chemotherapy treatment
• Use of targeted agents (e.g., monoclonal antibodies or kinase inhibitors) will not be counted as a prior chemotherapy treatment
• Patients with known EGFR-activating mutations or ALK rearrangements should have received treatment with a targeted kinase inhibitor (e.g., erlotinib, crizotinib) and no longer be considered as a candidate for such treatment
• Measurable disease according to RECIST 1.1
• ECOG performance status 0-1
• Resolution to Grade ≤ 1 Adverse Events, of all clinically significant toxic effects of prior therapy
• Adequate hematologic, hepatic, cardiac, and renal function
• Female patients of childbearing potential must have a negative serum or urine pregnancy test, whichever is considered standard by the institution

Exclusion Criteria:

• Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung or NSCLC NOS
• Prior therapy with pemetrexed
• Inability or unwillingness to take folic acid, vitamin B12 supplementation or corticosteroids
• Inability to discontinue non-steroidal anti-inflammatory drugs for 5 days (long half-life) or for 2 days (short half-life, if CrCL <80 mL/min) before pemetrexed dosing and until 2 days after pemetrexed dosing

• Leptomeningeal disease or any untreated or symptomatic brain metastases, unless the following criteria are met:

  • brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery
  • steroids are currently not required and more than 14 days since last steroid treatment
• Symptomatic pleural effusion (> CTCAE Grade 1 dyspnea) that is not amenable to drainage
• Treatment with other systemic anticancer therapy within 4 weeks prior to the first dose of study medication
• Treatment with full field radiation therapy within 4 weeks or limited field radiation therapy within 2 weeks prior to the first dose of study medication
• Major surgery within 4 weeks or minor surgery within 2 weeks prior the first dose of study medication
• Elective or a planned major surgery while on study treatment
• Radiation therapy to greater than 25% of the bone marrow
• Clinically significant active infection (e.g. tuberculosis, viral hepatitis, HIV)
• Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct
• Concurrent active malignancy other than adequately treated basal cell or squamous cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
• Pregnant or breast feeding
• Patients who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (Appendix F) or who have a history of long QT syndrome
• Patients who are taking medications that are strong inducers or inhibitors of CYP3A4