The purpose of this study is to determine if the use of exploratory immunologic biomarkers, functional MRI images can serve as early predictors for response of NSCLC. It also will provide important information on the perceived side effects from a patient perspective. Patients may participate if they have tumors ≥3 cm without lymph node involvement (for which chemotherapy is not part of the standard of care). Patients will only receive stereotactic body radiation therapy (SBRT) per standard dose guidelines.

Inclusion Criteria:

All patients:

• Histologically confirmed non-small cell lung cancer
• Medically or technically inoperable as per thoracic surgeon or patient's preference not to undergo surgical resection
• Age ≥ 18 years
• Women of childbearing potential must have a negative blood pregnancy test
• Ability to provide written informed consent

Cohort A:

• Stage IIA-IIIA (TanyN1M0 or T2b-4N0M0) Selected patients with single station N2 nodal involvement in close proximity to the primary tumor target may be considered eligible at the discretion of the PI if all normal tissue guidelines can be met

• Eligible for chemo-therapy

• Karnofsky Performance Status ≥70%

• Men and women of childbearing potential must be willing to use effective contraception while on treatment and for at least 3 months thereafter

• Patients must show adequate organ function as defined by:

  • Calculated creatinine clearance ≥40 mL/min for patients receiving pemetrexed (by Cockcroft-Gault)
  • Calculated creatinine clearance ≥30 mL/min for patients receiving gemcitabine or paclitaxel (by Cockcroft-Gault) Total bilirubin less than 1.5 x ULN (unless known Gilbert's disease)
  • AST and ALT less than 3 x ULN
  • Absolute neutrophil count greater than 1500/mm3
  • Platelet count greater than 100,000/mm3

Cohort B:

• T2a-4N0M0 who are not candidates for cohort A or who will not be treated with chemotherapy (due to patient preference or at the recommendation of the treating physician).

Exclusion Criteria:

All patients:

• Prior radiation therapy to the lungs
• Prior surgery or chemotherapy for this presentation of lung cancer (history of prior lung cancer that has been treated and deemed inactive by the clinician is acceptable. Recurrent tumors may be treated on protocol as long as SBRT will be the definitive treatment.)
• N2-3 lymph node involvement based on PET/EBUS-FNA/mediastinoscopy (Any N2 disease that is more than just minimal single station involvement is excluded)
• Direct tumor extension into including aorta or pulmonary artery
• Chronic corticosteroid use equivalent to ≥ prednisone 10 mg daily

Prior treatment with a CD137 agonist, ipilimumab, or the CTLA-4 inhibitor, or PD-1/PDL-1 inhibitor

• Unstable congestive heart failure

Cohort A:

• Continuous oxygen use

Patients meeting the following exclusion criteria will be excluded from the functional MRI portion only:

• Metallic implant,exclusions will be determined per institutional policies
• Pacemaker and defibrillators are excluded
• Stents etc. will be evaluated according to MSKCC policy
• Unmanageable claustrophobia
• High risk for nephrogenic systemic fibrosis