Neo-adjuvant Treatment in Non-Small Cell Lung Cancer (NSCLC)

OBJECTIVES:

• To evaluate the efficacy and safety of neoadjuvant sequential chemoimmunotherapy comprising cetuximab, cisplatin, and docetaxel before radiotherapy and cetuximab followed by surgery in patients with resectable stage IIIB non-small cell lung cancer.

OUTLINE: This is a multicenter study.

• Chemoimmunotherapy (courses 1-3): Patients receive chemoimmunotherapy comprising cetuximab IV over 1-2 hours on days 1, 8, and 15; cisplatin IV over 1 hour on days 1 and 2; and docetaxel IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) on days 3-8 or a single dose of pegfilgrastim the day after chemotherapy. Treatment repeats every 3 weeks for 3 courses.
• Radiotherapy (course 4): Beginning on day 1 of week 10, patients undergo 3-dimensional conformal or intensity-modulated radiotherapy 5 days a week for 3 weeks. Patients also receive cetuximab IV over 1 hour on days 1, 8, and 15.
• Surgery: Beginning 21-28 days after completion of radiotherapy, patients undergo surgery.

After completion of study treatment, patients are followed every 3 months for 2 years and every 6 months for 3 years.

DISEASE CHARACTERISTICS:

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

• Squamous, adeno, large cell, or poorly differentiated disease
• Stage IIIB disease (T4N0-3M0 or T1-4N3M0) according to 6th TNM classification

• Assessed by bronchoscopy and PET-CT scan within 42 days of registration
• No malignant pleural or pericardial effusion, invasion of the aorta, esophagus, myocardium, or supraclavicular
• No scalene nodes N3
• No stages IIIB disease defined only by satellite lesions in the same lobe
• Lymph node staging done by mediastinoscopy (or EBUS) in N+ disease on PET-CT scan (SUV above mediastinum background SUV) or CT (size > 10 mm in the smallest diameter) within 42 days of registration

• Fine needle aspiration biopsy must be done by EBUS, TBNA, or VATS if lymph nodes are not accessible by mediastinoscopy (ATS nodes #5/6)
• Mediastinoscopy is mandatory for suspicion of T4 tumor invading the trachea on PET-CT and CT scan in N-disease
• Measurable disease assessed by contrast-enhanced CT-scan within 28 days of registration
• Tumor tissue available for translational research (no cytology)
• Resectable disease based on a multidisciplinary tumor board decision
• No brain metastasis (confirmed by MRI within 42 days of registration)

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Platelet count ≥ 100 x 10^9/L
• Neutrophil count ≥ 1.5 x 10^9/L
• Bilirubin normal
• AST ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• FEV1 and DLCO ≥ 80% OR exercise test peak V02 > 75% or 20 mL kg^-1 min^-1 (for pneumonectomy)
• Exercise test peak V02 ≥ 35% and ≥ 10 mL kg^-1 min^-1 with predicted postoperative FEV1 and DLCO ≥ 30% (for resection less than pneumonectomy [resection up to calculated extend according to ESTS/ACCP guidelines])
• Ejection fraction > 45% assessed by echocardiography
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study therapy
• Must be compliant and geographically proximal for proper staging and follow-up
• No previous malignancy within the past 5 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
• No psychiatric disorder precluding understanding of information on trial-related topics and giving informed consent
• No preexisting peripheral neuropathy > grade 1
• No ischemia or relevant dysfunction revealed by noninvasive stress testing (stress radionuclide myocardial perfusion imaging or dobutamine stress echocardiography) for patients with a history of ischemic heart disease or any other relevant cardiovascular condition
• No unstable cardiac disease requiring treatment, congestive heart failure or angina pectoris even if medically controlled, significant arrhythmia, or myocardial infarction within the past 3 months
• No serious underlying medical condition that, at the judgment of the investigator, could impair the ability of the patient to participate in the trial (e.g., active autoimmune disease, uncontrolled diabetes, or uncontrolled infection)
• No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs
• No absolute contraindications for the use of corticosteroids as premedication

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy to the chest
• No pretreatment with any cytostatic therapy
• No concurrent corticosteroids, except for prophylactic medication regimen prior to treatment or treatment of acute hypersensitivity reactions or chronic treatment (initiated > 6 months prior to trial entry) at low-dose (< 20 mg methylprednisolone or equivalent)
• No concurrent drugs contraindicated for use with the trial drugs
• At least 30 days since prior and no other concurrent experimental drugs or other anticancer therapy on another clinical trial