Biomarker-Integrated Approach of Targeted Therapy for Lung Cancer Elimination Plus External Beam Radiation Therapy (BATTLE-XRT)

Inclusion Criteria:

1. Histologically or cytologically documented NSCLC, including squamous cell carcinoma, adenocarcinoma (including bronchoalveolar cell), and large cell anaplastic carcinoma (including giant and clear cell carcinomas) and poorly differentiated (not otherwise specified, NOS) non-small cell lung cancer; totally resected tumors are excluded. Patients should have tumor tissue for biomarker testing if available. Archival samples may be used. Patients without tissue for biomarker testing may be enrolled at the discretion of the investigator. The determination of MET status should be done by a pathologist who is trained in using the SP44 antibody with the Ventana platform and using the Ventana/Genentech algorithm.
2. Patients with T1or T2 disease with N2 or T3N1-2 disease (Stage IIIA) are eligible if they are deemed inoperable. Patients with T4 with any N or any T with N2 or N3 disease are eligible if unresectable. Patients may have limited stage M1 disease, with a maximum of 3 metastatic sites (including the single brain mets) only if the other sites are to be treated with definitive intent, unless they are no longer clinically present secondary to induction chemotherapy. Treatment to the other sites can be delivered prior to or after this trial. Measurable disease is required. See Response Evaluation Criteria in Solid Tumors (RECIST) definitions of measurable disease.
3. Patients must be \>/=18 years of age.
4. Patients with Zubrod performance status 0-2.
5. Adequate hematologic function defined as: ANC \>/= 1,500/mm3, platelets \>/= 100,000/mm3, and hemoglobin \>/= 9 g/dL (prior to transfusions); adequate hepatic function defined as: total bilirubin \</= 1.5 mg/dl, SGOT or SGPT \</= 3 x ULN, adequate renal function defined as a serum creatinine level \</= 2.0 mg/dl, alkaline phosphatase \</= 2.5 x ULN, glucose \</= 2 x ULN.
6. FEV1 with \>/= 1000 cc.
7. Patients with a pleural effusion that is a transudate, cytologically negative and nonbloody are eligible if the radiation oncologists feel the tumor can still be encompassed within a reasonable field of radiotherapy. If a pleural effusion can be seen on the chest computed tomography (CT) but not on chest x-ray (CXR) and is too small to tap, the patient is eligible.
8. If patients had exploratory thoracotomy, they must have recovered from the procedure (\</= grade 1 or baseline). Exploratory Thoracotomy and beginning of treatment should be within one month.
9. Women of childbearing potential (A woman of child-bearing potential is a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months \[i.e., who has had menses at any time in the preceding 24 consecutive months\]) and male participants must practice effective contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study and for four weeks after completion of treatment.
10. For women of childbearing potential, a urine or blood pregnancy test must be performed within 48 hours prior to the start of protocol treatment.
11. Prior induction chemotherapy will be allowed, as is prior target therapy. Patients with progression on an EGFR targeting agent will also be allowed, but stratified between the two arms.
12. Patients must sign a study-specific consent form prior to study entry.

Exclusion Criteria:

1. Active pulmonary infection not responsive to conventional antibiotics
2. History of interstitial lung disease.
3. History of severe chronic obstructive pulmonary disease (COPD) requiring \>/= 3 hospitalizations over the past year.
4. Significant history of cardiac disease, i.e., uncontrolled hypertension (i.e. can't reduce blood pressure (BP) below a systolic of 160 or diastolic of 100), unstable angina, uncompensated congestive heart failure, myocardial infarction within the past 2 months, or cardiac ventricular arrhythmias requiring medication.
5. Patients with \> grade 3 neuropathy.
6. Evidence of life threatening disease resulting in a life expectancy of less than 3 months.
7. Women who are pregnant or breast feeding, as treatment involves unforeseeable risks to the participant, embryo, fetus, or nursing infant; women with a positive pregnancy test on enrollment or prior to study drug administration.
8. Women of childbearing potential and male participants who are unwilling or unable to use an acceptable method of contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study and for four weeks after completion of treatment or those who are using a prohibited contraceptive method (methods with unknown efficacy).
9. Patients who currently are participating in other clinical trials and/or who have participated in other clinical trials (These patient may be enrolled but radiation must not start within 15 days of any previous experiment therapy).