In previous phase 2 studies, pemetrexed has shown antitumor activity in advanced non-small cell lung cancer as a single agent as well as in combination with cisplatin. Since the introduction of vitamin supplementation, pemetrexed has shown good tolerance and high safety. Vitamin supplementation has opened the opportunity to offer patients higher pemetrexed dosing, as has been demonstrated by a recent Phase 1 study. The higher dose with supplementation may increase pemetrexed's efficacy without unduly compromising safety. The present Phase 2 study will use pemetrexed dosing that is tailored to individual patient tolerance, and is an effort to determine the efficacy and safety of this approach in patients with advanced NSCLC who had prior chemotherapy.

Inclusion Criteria:

• diagnosis of NSCLC
• Locally advanced or metastatic disease (Stage IIIB or IV).
• Patients must have previously received one chemotherapy regimen for palliative therapy of locally advanced or metastatic disease.
• Disease status must be that of measurable disease as defined by RECIST criteria
• Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) Scale; and adequate organ function.

Exclusion Criteria:

• Known or suspected brain metastasis, or Second primary malignancy that is clinically detectable at the time of consideration for study enrollment
• Concurrent administration of any other tumor therapy.
• History of significant neurological or mental disorder, including seizures or dementia; or any other serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study
• Inability to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) 2 days before, the day of, and 2 days after the dose of pemetrexed.
• Inability or unwillingness to take folic acid, vitamin B12 supplementation, or dexamethasone