The goal of this clinical research study is to learn how effective the drug pemetrexed (ALIMTA®) is in treating advanced NSCLC in patients with poor performance status (PS) (inability to perform every day activities without difficulty).

Objectives:

Primary Objectives:

• PS = 2 cohort: Response
• PS = 3 cohort: Descriptive

Secondary Objectives:

• Tolerability of single agent pemetrexed (Alimta®) in PS = 3 NSCLC patients
• Improved symptoms (both cohorts)
• Molecular Correlative studies (both cohorts)
• Overall survival
• Time to progression

Pemetrexed is designed to block enzymes in the body that are important for tumor growth. Pemetrexed is commercially approved for the treatment of NSCLC but not for poor performance status patients.

If participants are found to be eligible to take part in this study, they will receive pemetrexed once every 3 weeks through a needle in their vein over about 10 minutes. Every 3 weeks is considered 1 treatment cycle. Once the treatment has started, they will return to the clinic before every treatment cycle. At these visits, they will have a physical exam, a performance status evaluation, and routine blood (about 3-4 teaspoons) and urine tests. They will have a chest x-ray and will be asked to complete a questionnaire about how you are feeling. they will also have a CT or MRI scan after Cycle 1 and every odd cycle from then on.

They are required to take folic acid by mouth every day for 5 days before the first dose of pemetrexed and continuing until 3 weeks after your last dose of pemetrexed. They will also receive an injection of vitamin B12 into your muscle before first dose of pemetrexed. The vitamin B12 injection will be repeated every 9 weeks until 3 weeks after their last dose of pemetrexed.

They will also to take a few low-dose steroid (dexamethasone) tablets twice a day before treatment, the day of treatment, and the day after each treatment. These will be taken to decrease the risk of rash and nausea caused by pemetrexed.

They may continue treatment with pemetrexed until your tumor grows or an unacceptable side effect occurs. They will be evaluated for symptoms 1-2 times per week while you are receiving treatment and then 2 weeks after stopping study treatment until 6 months after stopping treatment.

When they stop treatment on this study, they will have a physical exam, routine blood (3-4 teaspoons) and urine tests, and a chest x-ray. The study doctor may ask them to visit University of Texas MD Anderson Cancer Center or be contacted by phone for follow-up on how they are doing.

This is an investigational study. The FDA has approved pemetrexed for the treatment of advanced NSCLC after earlier treatment with chemotherapy, and for the treatment for malignant mesothelioma in combination with cisplatin. About 70 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Histologically or cytologically proven Stage IIIB (T4 lesion due to malignant pleural or pericardial effusion) or Stage IV. Clinically significant pleural or peritoneal effusions should be drained prior to dosing.
2. Zubrod PS 2 or PS 3
3. Patients with asymptomatic brain metastases and no requirement for corticosteroids or anticonvulsants are eligible for this clinical trial.
4. Measurable OR non-measurable disease documented by CT or MRI.
5. Patients may have had </=1 prior chemotherapy regimens but multiple prior biologic regimens. At least 4 weeks need to have elapsed since last chemotherapy or biologic therapy administration.
6. Prior radiation therapy is permitted; however, at least two weeks must have elapsed since the completion of prior radiation therapy and patients must have recovered from all associated toxicities at the time of registration. Measurable or non-measurable disease must be outside the previous radiation field OR patients with visible progression or new lesions within the radiation field are eligible.
7. At least two weeks must have elapsed since surgery and patients must have recovered from all associated toxicities at the time of registration.
8. Creatinine clearance >/= 45 cc/min measured or calculated using the following formula: Calculated Creatinine Clearance = (140 - age) X WT (kg) X (0.85 if female)/72 X creatinine (mg/dl) Calculated Creatinine Clearance = (140 - age) X WT (kg) X (1.00 if male)/72 X creatinine (mg/dl)
9. Absolute neutrophil count (ANC) >/= 1,500/µl
10. Platelet >/= 100,000/µl
11. ALT/AST: </=3.0 x upper limit of normal (ULN) except in known hepatic metastasis wherein may be </= 5 x ULN
12. Bilirubin: </=1.5 x ULN
13. Hemoglobin: >/=9.0 x 10^9/L
14. Patient must not be pregnant or breastfeeding. Patients of childbearing potential agree to practice an effective contraceptive method for the duration of the study.
15. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
16. Men and women, aged >/=18 years.

Exclusion Criteria:

1. Prior treatment with pemetrexed therapy.
2. Patients planning to receive any other concomitant anticancer treatment including chemotherapy, radiation therapy, biologic agents or any other investigational drugs.
3. Women who are pregnant or breastfeeding may not participate in this trial. All women of childbearing potential must have a negative pregnancy test within 24 hours prior to enrolling in the study.
4. Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents for a 5-day period (8-day period for long-acting agents, such as piroxicam).
5. Inability and unwillingness to take folic acid or vitamin B12 supplementation.
6. Inability to take corticosteroids.
7. Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission or other cancer from which the patient has been disease-free for >/= 5 years.

Adverse event data collected for three-week treatment cycle, up to four cycles or 12 weeks.