Inclusion Criteria:

• Suspected or histologic/cytologic diagnosis of NSCLC, not amenable to curative treatment with surgery or XRT. Encompasses advanced stage patients with select stage IIIB or stage IV. Histologic/cytologic documentation of recurrence is required in patients who were previously completely resected and now have metastatic disease.
• Fresh frozen tissue must be available to generate and apply the genomics predictor. If not obtained at the time of diagnosis, then subject must consent to another biopsy as a fresh tissue sample must yield adequate high quality RNA. If patient had prior XRT therapy, fresh frozen tissue biopsy for genomics analysis must be outside XRT field.
• At least one, non-radiated, measurable lesion by RECIST criteria.
• ECOG performance status of 0 or 1.
• NO prior chemo, biologic or targeted therapy for any malignancy. Prior therapy with low dose methotrexate or similar medications allowed if used for non-malignant conditions (i.e. arthritis, arteritis).
• Prior XRT therapy is permitted if ≥1 week since completion of XRT. XRT must be <25% of bone marrow reserve.
• Age greater than 18 years.
• No previous or concomitant malignancy in the past 5 years other than surgical management for carcinoma in situ of the cervix, breast, NSCLC, basal cell or squamous cell carcinoma of the skin.
• No other serious medical or psychiatric illness.
• Signed informed consent.

• Required lab data within 2 weeks of enrollment:

  1. ANC/AGC >1500 per uL
  2. Platelets >100,000 per uL
  3. Total bili <1.5 mg/dL
  4. Creatinine <2 mg/dL; creatinine clearance ≥45 ml/min.
  5. SGOT/SGPT ≤3x/ULN except in presence of known hepatic mets (may be up to 5x ULN).
• Females of child-bearing potential (not surgically sterilized and between menarche and 1 year post menopause) must test negative for pregnancy within 7 days prior to or at the time of enrollment based on a serum pregnancy test.
• Both sexually active males and females of reproductive potential must agree to use a reliable method of birth control, as determine by the patient and their health care team, during study and for 3 months following the last dose of study drug.

Exclusion Criteria:

• Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
• Concurrent administration of any other anti-tumor therapy (see #5 inclusion for exceptions).
• Inability to comply with protocol or study procedures.
• Active infection requiring IV antibiotics, antifungal or antiviral agents, that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
• Untreated documented symptomatic CNS metastases.
• Major surgery within 2 weeks of study or other serious concomitant systemic disorders that, in the opinion or the investigator, would compromise the safety of the patient or compromise the patient's ability to complete study.
• MI having occurred less than 6 months before inclusion, any known uncontrolled arrhythmia, symptomatic angina pectoris, active ischemia or cardiac failure not controlled by meds.
• Contraindications to corticosteroids.
• Inability/unwillingness to take folic acid or vitamin B12 supplementation.
• Unwillingness to stop taking herbal supplements while on study.
• Presence of clinically significant third-space fluid collections (for example, ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to treatment initiation and throughout study enrollment as the distribution of pemetrexed in this fluid space is not fully understood.
• Inability to discontinue administration of aspirin at a dose greater than 1300 mg/day or other non-steroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days for long-acting agents such as piroxicam).
• Female patients that are pregnant or breast-feeding.