Gefitinib in Treating Patients With Non-Small Cell Lung Cancer That Has Been Surgically Removed

• Disease free survival [ Time Frame: approxmately 3 years ] [ Designated as safety issue: No ]
• Prognostic significance of EGFR expression [ Time Frame: approxmately 3 years ] [ Designated as safety issue: No ]
• Toxicity of ZD1839 [ Time Frame: every 6 months ] [ Designated as safety issue: Yes ]
  Adverse events will be monitored on an ongoing basis by the central office and presented every 6 months in an unblinded fashion to the Data Safety Monitoring Committee of the NCIC CTG.

RATIONALE: Biological therapies such as gefitinib may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether gefitinib is effective in delaying the recurrence of non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying gefitinib to see how well it works compared to placebo in treating patients who have undergone surgery for stage IB, stage II, or stage IIIA non-small cell lung cancer.

OBJECTIVES:

Primary

• Compare the overall survival of patients with completely resected primary stage IB, II, or IIIA non-small cell lung cancer treated with gefitinib vs placebo.

Secondary

• Compare the disease-free survival of patients treated with these regimens.
• Determine the prognostic significance of epidermal growth factor receptor expression, phosphorylation, and mutations in the primary tumor in predicting relative impact of gefitinib on survival of these patients.
• Establish a comprehensive tumor bank linked to a clinical database for further study of molecular markers in patients treated with these regimens.
• Determine the toxicity of gefitinib in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease stage (IB vs II vs IIIA), histological subtype (squamous cell vs others), postoperative radiotherapy (yes vs no), prior adjuvant platinum-based chemotherapy (yes vs no), and gender. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral gefitinib daily, unless otherwise directed by the investigator.
• Arm II: Patients receive oral placebo daily, unless otherwise directed by the investigator.

Treatment in both arms continues for up to 2 years in the absence of disease progression or unacceptable toxicity.

Patients are followed at 1 month, 3 months, and every 3 months for 30 months after randomization, then every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,242 patients (621 per treatment arm) will be accrued for this study within 3.5 years.

• Drug: IRESSA (ZD1839)
  250mg daily oral dose for 2 years
• Other: Placebo comparator
  daily oral dose of 250mg tablet for 2yrs (matching placebo comparator)

• Active Comparator: IRESSA (ZD1839)
  Intervention: Drug: IRESSA (ZD1839)
• Placebo Comparator: Placebo
  Intervention: Other: Placebo comparator

DISEASE CHARACTERISTICS:

• Histologically confirmed primary non-small cell lung cancer (NSCLC)

  • Bronchoalveolar carcinoma presenting as discrete solitary radiological mass or nodule allowed
  • Stage IB, II, or IIIA disease

  • Completely resected by lobectomy, sleeve resection, bilobectomy, or pneumonectomy within the past 16 weeks (26 weeks for patients who received adjuvant platinum-based chemotherapy)

    • Mediastinal lymph node resection or lymph node sampling attempted with no evidence of metastatic involvement
    • Patients without a complete mediastinal lymph node resection or lymph node sampling must have undergone biopsy of any mediastinal lymph node measuring 1.5 cm or more on pre-surgical CT/MRI scan or any area of increased uptake in the mediastinum on pre-surgical PET scan
• No combination of small cell and non-small cell carcinoma or pulmonary carcinoid tumor
• No more than 1 discrete area of apparent primary cancer (even within the same lobe)

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm^3
• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin normal
• AST/ALT no greater than 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 2.5 times ULN

Renal

• Creatinine no greater than 1.5 times ULN

Cardiovascular

• No uncontrolled congestive heart failure
• No angina
• No arrhythmias

Other

• No active uncontrolled infection
• No clinically significant or untreated ophthalmologic conditions (e.g., Sjögren's syndrome)
• No clinically significant or untreated gastrointestinal conditions (e.g., Crohn's disease or ulcerative colitis)
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix
• No other concurrent malignancy
• No prior allergic reaction to compounds of similar chemical or biological composition to gefitinib
• No history of psychiatric or neurologic disorder that would preclude study compliance
• No active pathological condition that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior neoadjuvant immunotherapy for NSCLC

Chemotherapy

• See Disease Characteristics
• Prior adjuvant platinum-based chemotherapy allowed
• At least 3 weeks since prior adjuvant platinum-based chemotherapy for NSCLC and recovered
• No prior non-platinum-based chemotherapy
• No prior neoadjuvant chemotherapy for NSCLC

Endocrine therapy

• Not specified

Radiotherapy

• Prior preoperative limited-field, low-dose external beam radiotherapy (less than 1,000 cGy) or endobronchial brachytherapy allowed
• At least 3 weeks since prior radiotherapy and recovered
• No prior full-dose preoperative radiotherapy with curative intent

Surgery

• See Disease Characteristics
• Recovered from prior oncologic or other major surgery

Other

• Prior laser therapy for short-term control of hemoptysis or lobar obstruction allowed
• No other concurrent anticancer therapy
• No concurrent drugs that induce CYP3A4 enzymes (e.g., phenytoin, carbamazepine, barbiturates, rifampin, or Hypericum perforatum [St. John's wort])

• National Cancer Institute (NCI)
• Eastern Cooperative Oncology Group
• Southwest Oncology Group