Ipilimumab, Nivolumab, and Stereotactic Body Radiation Therapy in Treating Patients with Stage IV Non-small Cell Lung Cancer

Inclusion Criteria

• Have a histologic diagnosis of stage IV NSCLC
• Be willing and able to provide written informed consent/assent for the trial
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 including at least ONE metastatic lesions that meet criteria for SBRT radiation * 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases) approximately 5 cm in maximal dimension; tumors larger than 65 cc can be partially treated
• For (optional) biopsy identified patients already undergoing diagnostic biopsy or marker placement: Be willing to undergo extra pass of tissue collection during treatment and/or after radiation
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 10 days of treatment initiation)
• Platelets >= 100,000 / mcL (performed within 10 days of treatment initiation)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 10 days of treatment initiation)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated (creatinine clearance should be calculated per institutional standard) creatinine clearance >= 50 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (performed within 10 days of treatment initiation)
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 10 days of treatment initiation)
• Albumin >= 3.0 mg/dL (performed within 10 days of treatment initiation)
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
• Have an investigator determined life expectancy of at least 6 months
• EXPANSION COHORTS CONCURRENT NIVOLUMAB (N)/IPILIMUMAB (I): Patients must meet all inclusion and exclusion criteria outlined. No patients with EGFR activating mutations or ALK translocations will be allowed

Exclusion Criteria

• Has received prior chemotherapy for NSCLC with the exception of neoadjuvant or adjuvant platinum-based chemotherapy for NSCLC completed > 6 months prior to enrollment
• Has prior exposure to anti-PD1/PD-L1 or anti-CTLA4 therapy
• Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation or ALK translocation, regardless of prior TKI
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of > 10 mg prednisone daily or equivalent at time of first dose of trial treatment
• Has a known history of active TB (Bacillus tuberculosis)
• Hypersensitivity to nivolumab, ipilimumab, or any of its excipients
• Has received radiation therapy within 2 weeks of study drug administration
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Patients with uncontrolled brain metastases; patients with controlled brain metastases will be allowed on protocol; controlled brain metastases will be defined as treated brain metastases; brain metastases will be considered “treated” on the day of surgical resection or the first day of radiation therapy (stereotactic radiosurgery [SRS] or whole body radiation therapy [WBRT]) depending on the treatment method; if patients require radiation therapy after surgery, they will still be considered “treated” on the day of surgery; however, all treatment for brain metastases must be completed prior to the initiation of protocol therapy; no follow up imaging is required prior to the start of protocol therapy
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known history of non-infectious pneumonitis that required steroids or active pneumonitis
• Has evidence of interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
• If known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) then patient is not eligible for cohorts including SBRT to liver lesions
• Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• Has had prior radiation therapy (defined as > 10% of prior prescription dose) to the area planning to be treated with SBRT