Inclusion Criteria:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

- Stage IIIB or IV disease

- Must have evidence of disease progression after first-line therapy

- Measurable or non-measurable disease

- Measurable disease is defined as lesions that can be accurately measured in ≥ 1
dimension as ≥ 2 cm by conventional techniques or ≥ 1 cm by spiral CT scan

- Non-measurable disease is defined as all other lesions, including small lesions
(i.e., longest diameter < 20 mm by conventional techniques or < 10 mm by spiral
CT scan) and truly non-measurable lesions, including any of the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural or pericardial effusion

- Lymphangitis cutis or pulmonis

- Abdominal mass that are not confirmed and followed by imaging techniques

- Cystic lesions

- No cavitary lesions

- No pleural effusions or ascites detectable on physical exam

- No symptomatic or untreated CNS metastases

- Patients with CNS metastases are eligible provided the metastases were
definitively treated with surgery or radiotherapy AND patient is asymptomatic
and off steroids or on a stable dose of steroids for 2 weeks prior to study
entry

- Concurrent enrollment on CALGB-580702 (imaging study) required

- ECOG performance status 0-1

- Granulocytes ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Magnesium ≥ lower limit of normal

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- PTT ≤ 1.5 times ULN

- INR ≤ 1.5

- Creatinine clearance ≥ 45 mL/min

- Quantitative urine protein < 30 mg/dL OR ≤ 1+ on dipstick

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
completion of study therapy

- QTc interval ≤ 500 msec within the past 2 years

- No ongoing cardiac dysrhythmias

- No atrial fibrillation

- No symptomatic congestive heart failure within the past 12 months

- NYHA class I heart failure allowed

- Patients with a history of NYHA class II heart failure are eligible provided at
least 1 of the following criteria is met:

- Asymptomatic on treatment

- Previously treated with anthracycline

- Previously treated with central thoracic radiotherapy that included the
heart in the radiotherapy port

- No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft or stenting, cerebrovascular accident, or transient ischemic attack within the
past year

- No hypertension that cannot be controlled by medications (i.e., blood pressure >
150/100 mm Hg despite optimal medical therapy)

- No history of venous thrombosis, pulmonary embolism, or hypercoagulopathy syndrome

- No history of pulmonary hemorrhage, bleeding diathesis, or evidence of hemoptysis

- Patients with blood-tinged or blood-streaked sputum are eligible provided the
hemoptysis is < 5 mL of blood per episode and < 10 mL of blood per 24-hour
period, in the best estimate of the investigator

- No abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or
serious or non-healing wound, ulcer, or bone fracture within the past 28 days

- History of hypothyroidism allowed provided patient is currently euthyroid

- At least 28 days since prior first-line therapy

- No more than one prior chemotherapy regimen (platinum or non-platinum based) in
the first-line setting for NSCLC

- Prior adjuvant therapy allowed provided the patient received one regimen in the
advanced setting

- At least 4 weeks since prior EGFR inhibitors or bevacizumab

- At least 28 days since prior major surgery (6 weeks since resection of brain
metastases)

- At least 14 days since prior radiotherapy

- More than 7 days since prior and no concurrent CYP3A4 inhibitors, including any of
the following:

- Azole antifungals (e.g., ketoconazole or itraconazole)

- Diltiazem

- Clarithromycin

- Erythromycin

- Verapamil

- Delavirdine

- HIV protease inhibitors (e.g., indinavir, saquinavir, ritonavir, atazanavir, or
nelfinavir)

- More than 12 days since prior and no concurrent CYP3A4 inducers, including any of the
following:

- Rifampin

- Rifabutin

- Carbamazepine

- Phenobarbital

- Phenytoin

- St. John's wort

- Efavirenz

- Tipranavir

- No prior pemetrexed disodium

- No prior VEGFR inhibitors (e.g., semaxanib, SU6668, AZ6474, sunitinib malate,
vatalanib, cediranib, AEE-788, or sorafenib)

- No concurrent chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal
anti-inflammatory agents known to inhibit platelet function

- No concurrent dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix),
and/or cilostazol (Pletal)

- No concurrent therapeutic anticoagulation for thromboembolic disease

- Concurrent low-dose warfarin (≤ 2 mg/day) allowed for prophylaxis of thrombosis

- No concurrent agents with proarrhythmic potential (e.g., quinidine, procainamide,
disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, or
flecainide)

- No concurrent hormonal therapy, except steroids for adrenal failure, hormones for
non-disease-related conditions (e.g., insulin for diabetes), or dexamethasone used
intermittently as an antiemetic or as premedication for pemetrexed disodium

- No other concurrent chemotherapy

- No concurrent palliative radiotherapy

- No concurrent G-CSF (filgrastim), GM-CSF (sargramostim), and/or pegfilgrastim