Pemetrexed Disodium or Erlotinib Hydrochloride as Second-Line Therapy in Treating Patients With Advanced Non-small Cell Lung Cancer

Inclusion Criteria:

Documented recurrence or disease progression of NSCLC

NSCLC must be confirmed by pathologic examination, either on initial diagnosis or disease recurrence/progression; mixed histology allowed if all components consistent with NSCLC
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 computed tomography (CT); if spiral CT is used, it must be used for both pre- and post- treatment tumor assessments

Prior radiation therapy is permitted as long as:

Recovered from the toxic effects of radiation treatment before study entry, except for alopecia
=< 25% of bone marrow radiated
Presence of measurable disease whether in-field disease progression/recurrence or disease outside the treatment fields of radiation port
Absolute neutrophil count (ANC) >= 1,500 uL
Platelet (PLT) >= 100,000 uL
Hemoglobin (Hgb) >= 10 g/dL
Total bilirubin: within normal institutional limits (WNL) OR direct bilirubin =< upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
International normalized ratio (INR) =< 1.5
Calculated creatinine clearance >= 45 mL/min using the Cockcroft-Gault formula
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
Negative pregnancy test done =< 7 days prior to pre-registration, for women of childbearing potential only
Ability to provide informed consent
Life expectancy >= 12 weeks
Tissue available and willing to submit tissue for central pathology review and EGFR evaluation; performed on original diagnostic/recurrent tissue (preferably paraffin-embedded tissue blocks); if institution unable to release tissue blocks, willing to submit 25 unstained slides (15 sections cut at 5 microns mounted on charged slides and 10 sections cut at 10 microns mounted on uncharged slides)
Must be previously treated for advanced disease with only 1 chemotherapy regimen which must contain cytotoxic agent(s); adjuvant/neoadjuvant treatment with cytotoxic agent(s) administered < 12 months (from date chemotherapy was started) prior to pre-registration will be considered as one prior treatment; NOTE: adjuvant/neoadjuvant treatment administered >= 12 months, use of targeted agents such as monoclonal antibodies prior to pre-registration will NOT be counted as one prior treatment; patient could have had adjuvant/neoadjuvant chemotherapy >= 12 months and 1 systemic chemotherapy regimen for metastatic or recurrent disease
Able to take folic acid, vitamin B12 supplementation, and dexamethasone
Able to permanently discontinue aspirin dose of >= 1.3 grams/day >= 10 days before and after pemetrexed treatment
Fertile patients must use effective contraception
Able to take folic acid, vitamin B_12 supplementation, and dexamethasone
Stable brain metastasis that have been treated with either whole brain radiation therapy or gamma knife surgery and are off steroid treatment for > 14 days prior to pre-registration, if applicable
Willingness to return to enrolling institution for treatment and follow-up

Exclusion Criteria:

Any of the following:

Pregnant women
Nursing women
Men or women of childbearing potential who are unwilling to employ adequate contraception
Any clinically significant infection, at the treating physician's discretion
Known human immunodeficiency virus (HIV) positive patients
Impairment of 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, bowel obstruction, etc)
Serious condition that, in the opinion of the investigator, would compromise the patient's ability to complete the study or increase the risk for serious adverse events

Any of the following prior therapies:

Prior radiation to > 25% of bone marrow
EGFR tyrosine kinase inhibitors
Pemetrexed
Chemotherapy =< 3 weeks prior to pre-registration
Mitomycin C/nitrosoureas =< 6 weeks prior to pre-registration
Immunotherapy =< 2 weeks prior to pre-registration
Biologic therapy =< 2 weeks prior to pre-registration
Gene therapy =< 2 weeks prior to pre-registration
Full field radiation therapy =< 4 weeks prior to pre-registration
Limited field radiation therapy =< 2 weeks prior to pre-registration
Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury =< 4 weeks prior to pre-registration or anticipation of need for major surgical procedure during the course of the study; minor surgery =< 2 weeks prior to pre-registration; insertion of a vascular access device is not considered major or minor surgery in this regard
Other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) =< 4 weeks prior to pre-registration
Steroid therapy for brain metastasis =< 14 days prior to pre-registration
Symptomatic serosal effusion (>= Common Terminology Criteria for Adverse Events [CTCAE] v3.0 grade 2 dyspnea) that is not amenable to drainage prior to pre-registration
Other invasive solid or hematologic malignancy; exceptions: prior malignancy was diagnosed and definitively treated >= 5 years previously with no subsequent evidence of recurrence; patients with a history of low-grade (Gleason score =< 6) localized prostate cancer will be eligible even if diagnosed < 3 years prior to pre-registration; these patients may continue on medications concomitantly to maintain their disease remission as necessary; patients with carcinoma in situ, regardless of organ involvement, or non-melanoma cutaneous carcinomas are eligible if these were definitively treated >= 3 years previously with no subsequent evidence of recurrence; Note: patients with breast cancer that was definitively treated > 5 years earlier but continue to receive aromatase inhibitors are NOT eligible

Only non-measurable disease, defined as all other lesions, including small lesions whose longest diameter measures < 2 cm with conventional techniques or < 1.0 cm with spiral CT, and truly non-measurable lesions, which include the following as per Response Evaluation Criteria In Solid Tumors (RECIST) criteria dated June 1999:

Bone lesions
Leptomeningeal disease
Ascites
Pleural/pericardial effusion
Inflammatory breast disease
Lymphangitis cutis/pulmonis
Abdominal masses that are not confirmed and followed by imaging techniques
Cystic lesions
Single disease site in prior radiation field

Any of the following concurrent severe and/or uncontrolled medical conditions:

Angina pectoris
History of congestive heart failure =< 3 months prior to pre-registration, unless ejection fraction > 40%
Myocardial infarction =< 6 months prior to pre-registration
Cardiac arrhythmia
Diabetes mellitus
Hypertension
Any other severe underlying diseases which are, in the judgment of the investigator, inappropriate for entry into this study
Respiratory symptoms > CTCAE grade 1