Grid Radiation Therapy for the Treatment of Stage IV Non-Small Cell Lung Cancer

Inclusion Criteria:

• Age ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2

• Stage IV non-small cell lung cancer progressing on standard of care first lineimmunotherapy or chemoimmunotherapy

• Patients have not had stereotactic body radiotherapy (SBRT) ≤ 30 days prior toregistration

• Extracranial lesion ≥ 3 cm amenable to grid therapy

• Patients with brain metastases are permitted to enroll if all of the followingare true:

• They are stable (without evidence of progression by imaging ≤ 30 daysprior to enrollment and any neurologic symptoms have returned to baseline)

• Have no evidence of new or enlarging brain metastases, and

• Are not using steroids ≤ 14 days prior to enrollment

• Patients may receive conventional palliative radiation to up to 2 othermetastatic sites (with at least one evaluable non-irradiated lesion)

• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 15 days prior to enrollment)

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to enrollment)

• Platelet count ≥ 100,000/mm^3 (obtained ≤ 15 days prior to enrollment)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or direct bilirubin ≤ ULN iftotal bilirubin is > 1.5 x ULN (obtained ≤ 15 days prior to enrollment)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 xULN for patients with liver involvement) (obtained ≤ 15 days prior to enrollment)

• Creatinine ≤ 1.5 x ULN OR glomerular filtration rate (GFR) > 60 mL/min for patientswith creatinine > 1.5 x ULN (obtained ≤ 15 days prior to enrollment)

• Negative pregnancy test done ≤ 7 days prior to registration for females ofchildbearing potential only

• Provide written informed consent

• Willing to provide mandatory blood specimens for correlative research

• Willing to return to Mayo Clinic for follow-up (during the Active Monitoring Phaseof the study)

• Estimated by investigator to have a life expectancy > 3 months

Exclusion Criteria:

• Co-morbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens

• Active autoimmune disease requiring systemic treatment, documented history of severeautoimmune disease, or a syndrome that requires systemic steroids orimmunosuppressive agents

• NOTE: Exceptions are allowed for:

• Vitiligo

• Resolved childhood asthma/atopy

• Intermittent use of bronchodilators or inhaled steroids

• Daily steroids at dose of ≤ 10mg of prednisone (or equivalent)

• Local steroid injections

• Stable hypothyroidism on replacement therapy

• Stable diabetes mellitus on non-insulin therapy

• Sjogren's syndrome

• Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection requiring systemic therapy

• Interstitial lung disease

• Serious, chronic gastrointestinal conditions associated with diarrhea (e.g.,Crohn's disease or others)

• Known active hepatitis B (i.e., known positive hepatitis B virus [HBV] surfaceantigen [HBsAg] reactive) • Known active hepatitis C (i.e., positive for hepatitis C virus [HCV]ribonucleic acid [RNA] detected by polymerase chain reaction [PCR])

• Known active tuberculosis (TB)

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Unstable cardiac arrhythmia

• Psychiatric illness/social situations that would limit compliance with studyrequirements (e.g., substance abuse)

• History of myocardial infarction ≤ 6 months, or congestive heart failure requiringuse of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Receiving any other investigational agent which would be considered as a treatmentfor the primary neoplasm

• Hypersensitivity to immunotherapy

• Previous adverse event attributed to immunotherapy that led to drug discontinuation

• History of grade 3+ immune-related adverse event or any grade of immune-relatedneurologic or ocular adverse event while receiving immunotherapy

• Note: Patients who had endocrine adverse events ≤ grade 2 are allowed to enrollif they are stable on appropriate replacement therapy and asymptomatic

• Other active malignancy < 6 months prior to registration

• EXCEPTIONS: Non-melanotic skin cancer, papillary thyroid cancer, prostatecancer, or carcinoma-in-situ of the cervix, or others curatively treated andnow considered to be at less than 30% risk of relapse

• History of allogenic organ transplantation

• History of active primary immunodeficiency

• Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that mayinclude clinical history, physical examination and radiographic findings, ortuberculosis testing in line with local practice)

• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti-HBc and absence of HBsAg) are eligible. Participants positive forHCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA