Inclusion Criteria:

- Histologically confirmed non-small cell lung cancer (NSCLC), either oninitial
diagnosis or at the time of disease recurrence/progression

- Mixed histology allowed if all components are consistent with NSCLC

- Recurrent or progressive disease

- Measurable disease, defined as at least one lesion whose longest diameter can be
accurately measured as ≥ 2.0 cm by conventional techniques or as ≥ 1.0 cm by spiral
CT scan

- Measurable disease must be outside of any previously irradiated treatment
field(s) unless there is disease progression or recurrence within the irradiated
field(s)

- No nonmeasurable disease only, defined as any of the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Abdominal masses not confirmed and followed by imaging techniques

- Cystic lesions

- Single disease site in prior radiotherapy field

- Tumor tissue samples must be available and adequate for epidermal growth factor
receptor (EGFR) evaluation by FISH

- Previously treated with only one cytotoxic chemotherapy regimen for advanced disease

- Neoadjuvant/adjuvant cytotoxic chemotherapy administered< 12 months (from date
chemotherapy was started) prior to study entry will be counted as one prior
treatment

- Neoadjuvant/adjuvant chemotherapy administered ≥ 12 months prior to study entry
and use of targeted agents (e.g., monoclonal antibodies) will not be counted as
one prior treatment

- No symptomatic serosal effusion (≥ grade 2 dyspnea as measured by CTCAE v3.0) that is
not amenable to drainage

- No brain metastasis, unless the following criteria are met:

- Brain metastasis is stable and has been previously treated with either
whole-brain radiotherapy or gamma-knife surgery

- More than 14 days since prior steroid treatment

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 10 g/dL

- Total bilirubin normal (ULN) OR direct bilirubinnormal

- AST and ALT ≤ 2.5 times ULN

- INR ≤ 1.5

- Creatinine clearance ≥ 45 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to take folic acid, vitamin B_12 supplementation, and dexamethasone

- No known HIV positivity

- No clinically significant infection

- No impaired gastrointestinal (GI) function, inability to swallow pills in the absence
of a feeding tube, or GI disease that may significantly alter absorption of oral
medications (e.g., ulcerative disease, uncontrolled nausea and vomiting,
malabsorption syndromes, or bowel obstruction)

- No serious condition that, in the opinion of the investigator, would preclude the
patient's ability to complete the study therapy or increase the risk for serious
adverse events

- No other invasive malignant solid tumor or hematologic malignancy, except for any of
the following:

- Prior carcinoma in situ, regardless of organ involvement, or nonmelanoma
cutaneous carcinoma that was definitively treated ≥ 3 years ago with no
subsequent evidence of recurrence

- Other prior malignancy diagnosed and definitively treated ≥ 5 years ago with no
subsequent evidence of recurrence

- Prior breast cancer that was definitively treated > 5 years ago allowed
provided patient is not receiving aromatase inhibitors

- Prio rlow-grade (Gleason score ≤ 6) localized prostate cancer that was
diagnosed < 3 years ago allowed

- Concurrent medications to maintain disease remission allowed

- No concurrent severe and/or uncontrolled medical condition, including any of the
following:

- Angina pectoris

- Congestive heart failure within the past 3 months, unless ejection fraction >
40%

- Myocardial infarction within the past 6 months

- Cardiac arrhythmia

- Diabetes mellitus

- Hypertension

- Any other severe underlying disease that, in the judgment of the investigator,
would preclude study entry

- No respiratory symptoms > CTCAE grade 1

- No significant traumatic injury within the past 4 weeks

- No concurrent prophylactic colony-stimulating factors

- Recovered from prior radiotherapy, except for alopecia

- No prior radiotherapy to > 25% of bone marrow

- No prior EGFR tyrosine kinase inhibitors or pemetrexed disodium

- More than 3 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)

- More than 2 weeks since prior immunotherapy, gene therapy, or other biologic therapy

- More than 2 weeks since prior limited-field radiotherapy (4 weeks for full-field
radiotherapy)

- More than 2 weeks since prior minor surgery*

- More than 4 weeks since prior major surgery (i.e., laparotomy)* or open biopsy

- More than 4 weeks since prior hormonal therapy

- More than 4 weeks since prior and no other concurrent ancillary therapy considered
investigational (i.e., utilized for a non-FDA-approved indication and in the context
of a research investigation)

- No aspirin dose ≥ 1.3 g/day for ≥ 10days before, during, and for ≥ 10 days after
treatment with pemetrexed disodium

- No other concurrent chemotherapy, immunotherapy, hormonal therapy, or radiotherapy

- Radiotherapy for symptom palliation (e.g., painful pre-existing bony metastasis)
allowed

- No other concurrent anticancer therapy

- No concurrent major surgery

- No concurrent antiretroviral therapy