• Overall survival, confirmed response rate, and adverse event profile based on epidermal growth factor receptor (EGFR)-FISH status (positive vs negative) [ Designated as safety issue: Yes ]
• Progression-free survival, overall survival, confirmed response rate, and adverse event profile based on EGFR gene mutation status [ Designated as safety issue: Yes ]
• Progression-free survival, overall survival, confirmed response rate, and adverse event profile based on EGFR expression as measured by immunohistochemistry (IHC) [ Designated as safety issue: Yes ]
• Prognostic effect of EGFR copy number, EGFR expression, and EGFR mutation status on outcome [ Designated as safety issue: No ]

RATIONALE: Pemetrexed and erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed is more effective than erlotinib in treating advanced non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying pemetrexed to see how well it works compared with erlotinib when given as second-line therapy in treating patients with advanced non-small cell lung cancer.

OBJECTIVES:

Primary

• Compare the progression-free survival of epidermal growth factor receptor (EGFR) FISH-positive or -negative patients with advanced non-small cell lung cancer treated with erlotinib hydrochloride versus pemetrexed disodium as second-line therapy.

Secondary

• Compare the overall survival, confirmed response rate, and adverse event profile in these patients based on EGFR-FISH status (positive vs negative).
• Compare the progression-free survival, overall survival, confirmed response rate, and adverse event profile in these patients based on EGFR expression as measured by immunohistochemistry (IHC).
• Compare the progression-free survival, overall survival, confirmed response rate, and adverse event profile in these patients based on EGFR gene mutation status.
• Evaluate the prognostic effect of EGFR copy number, as measured by FISH, on the outcome of these patients.
• Evaluate the prognostic effect of EGFR expression, as measured by IHC, on the outcome of these patients.
• Evaluate the prognostic effect of EGFR mutation status on the outcome of these patients.
• Prospectively test the hypothesis that functionally relevant polymorphisms in the genes encoding for pemetrexed disodium targets, as well as genes encoding for one or more of the key enzymes involved in the transport, activation, and inactivation of pemetrexed disodium, either singly or in combination, play a role in the efficacy and/or toxicity of pemetrexed disodium.
• Prospectively test the hypothesis that functionally relevant polymorphisms in the EGFR gene as well as genes encoding for one or more of the key enzymes involved in the metabolism of erlotinib hydrochloride, either singly or in combination, play a role in the efficacy and/or toxicity of erlotinib hydrochloride.
• Evaluate proteomic signatures in blood samples as predictors of survival and response to treatment with erlotinib hydrochloride.
• Evaluate thymidylate synthase, dihydrofolate reductase, GAR formyltransferase, and methylthioadenosine phosphorylase gene expression in tumor samples, as measured by IHC or quantitative polymerase chain reaction, as predictors of survival and response to treatment with pemetrexed disodium.
• Evaluate the Ras mutation status, EGFR mutation status, and epithelial to mesenchymal transition status (E-cadherin expression and vimentin expression) in tumor samples, as measured by IHC, as predictors of survival and response to treatment with erlotinib hydrochloride.

OUTLINE: This is a multicenter study. Patients are stratified according to FISH status (negative vs positive), ECOG performance status (0 vs 1 vs 2), gender, smoking status (never smoked vs light smoker [≤ 15 pack years] vs heavy smoker [> 15 pack years]), disease histology (adenocarcinoma vs other), and best response to prior chemotherapy (complete response/partial response vs stable disease vs progressive disease). Patients are randomized to

1 of 2 treatment arms.

• Arm I: Patients receive oral erlotinib hydrochloride once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Tumor tissue samples are collected at baseline for correlative laboratory studies, including analysis of epidermal growth factor receptor (EGFR) gene expression by FISH; EGFR protein expression by immunohistochemistry (IHC); EGFR and K-ras mutation status; epithelial to mesenchymal transition status (E-cadherin expression and vimentin expression) by IHC; thymidylate synthase, dihydrofolate reductase, and GAR formyltransferase gene expression by quantitative polymerase chain reaction; and methylthioadenosine phosphorylase gene expression by IHC.

After completion of study therapy, patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.

• Drug: erlotinib hydrochloride
• Drug: pemetrexed disodium

• Experimental: Patients receive oral erlotinib hydrochloride once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
• Experimental: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

DISEASE CHARACTERISTICS:

• Histologically confirmed non-small cell lung cancer (NSCLC), either on initial 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 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

PATIENT CHARACTERISTICS:

• 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 bilirubin normal
• 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

    • Prior low-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

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• 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 ≥ 10 days 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
• No concurrent prophylactic colony-stimulating factors NOTE: *Insertion of a vascular access device is not considered major or minor surgery

• National Cancer Institute (NCI)
• Cancer and Leukemia Group B
• Eastern Cooperative Oncology Group
• Southwest Oncology Group
• National Cancer Institute of Canada