Inclusion Criteria:

- Confirmed Stage IIIB/ IV non-small cell lung cancer (NSCLC).

- Relapsed after treatment with 1 or 2 prior chemotherapy regimens, including at least
1 platinum-based treatment. Patients may have received pemetrexed as 1 of the prior
therapies. Patients may not have received investigational therapy as their only prior
therapy.

- Recovered from the toxic effects of prior therapy.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- Smoked ≥ 100 cigarettes in their lifetime, whether a former or current cigarette
smoker.

- Adequate blood, liver and kidney function as defined by laboratory values.

- Received 1-1.25 mg daily oral folic acid for at least 7 days prior to randomization
and 1 mg intramuscular injection of vitamin B12 within 10 weeks prior to
randomization.

- Women of childbearing potential must use medically acceptable birth control and have
a negative serum pregnancy test within 14 days prior to randomization. Patients who
are postmenopausal for at least 1 year (> 12 months since last menses) or are
surgically sterilized do not require this test.

- Men who are not surgically sterile must use medically safe and effective birth
control from the time of study randomization, and agree to continue practicing until
at least 90 days after the last administration of study treatment.

- Accessible for repeat dosing and follow-up.

- Give written informed consent.

Exclusion Criteria:

- Active concurrent primary malignancy (except non-melanoma skin cancer or in situ
carcinoma of the cervix). If there is a history of prior malignancy, the patient must
be disease-free for ≥ 5 years. Patients with other prior malignancies less than 5
years before study entry may still be enrolled if they have received treatment
resulting in complete resolution of the cancer and currently have no evidence of
active or recurrent disease.

- Use of investigational drugs, biologics, or devices within 4 weeks prior to
randomization.

- Previous exposure to pralatrexate or erlotinib.

- Women who are pregnant or breastfeeding.

- Congestive Heart Failure Class III/IV according to New York Heart Association (NYHA)
Functional Classification.

- Uncontrolled hypertension.

- Human immunodeficiency virus (HIV)-positive diagnosis with a CD4 count of <100 mm3 or
detectable viral load within the past 3 months, and is receiving combination
anti-retroviral therapy.

- Symptomatic central nervous system metastases or lesions for which treatment is
required.

- Major surgery within 2 weeks of study randomization.

- Receipt of any conventional systemic chemotherapy within 4 weeks (6 weeks for
nitrosoureas, mitomycin C), or radiation therapy (RT) within 2 weeks, prior to
randomization.

- Active infection or any serious underlying medical condition, which would impair the
ability of the patient to receive protocol treatment.

- Dementia or significantly altered mental status that would prohibit the understanding
and giving of informed consent or limit study compliance.