Inclusion Criteria:

• Age ≥ 18 years.
• ECOG 0-2.
• Stage IV non-small cell lung cancer progressing on standard of care first line immunotherapy or chemoimmunotherapy.
• Extracranial lesion > 4 cm amenable to grid therapy.
• Patients with brain metastases are permitted to enroll all of the following are true:
• They are stable (without evidence of progression by imaging ≤ 4 weeks prior to registration 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 registration.
• Patients who have not had SBRT within 1 month of enrolment
• Patients may receive conventional palliative radiation up to 2 other metastatic sites (with at least one evaluable non irradiated lesion)
• The following laboratory values obtained ≤ 15 days prior to registration:
  • Hemoglobin ≥ 9.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN if total bilirubin is > 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Creatinine OR glomerular filtration rate (GFR) ≤ 1.5 x ULN OR GFR > 60 mL/min for patients with creatinine > 1.5 x ULN.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Persons able to become pregnant OR able to father a child must be willing to use an adequate method of contraception while on treatment and for 120 days after last treatment.
• Provide written informed consent.
• Willing to provide mandatory blood specimens for correlative research.
• Willing to return to Mayo Clinic or Washington University for follow-up (during the Active Monitoring Phase of the study).
• Known life expectancy of > 3 months.

Exclusion Criteria:

Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown:

• Pregnant persons.
• Nursing persons.
• Persons of childbearing potential OR able to father a child who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Active autoimmune disease requiring systemic treatment, documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive 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;
    • Sjögren’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 HBV surface antigen (HBsAg) reactive);
  • Known active hepatitis C (i.e., positive for HCV RNA detected by PCR);
  • Known active tuberculosis (TB);
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Unstable cardiac arrhythmia; or
  • Psychiatric illness/social situations that would limit compliance with study requirements (e.g., substance abuse).
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Hypersensitivity to immunotherapy.
• Previous adverse event attributed to immunotherapy that led to drug discontinuation.
• Previous receipt of dual checkpoint blockade, for example with nivolumab and ipilimumab.
• History of Grade ≥ 3 immune-related adverse event or any grade of immune-related neurologic or ocular adverse event while receiving immunotherapy
  • Note: Patients who had endocrine adverse events ≤ Grade 2 are allowed to enroll if 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, prostate cancer, or carcinoma-in-situ of the cervix, or others curatively treated and now considered to be at less than 30% risk of relapse.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
  • Note: Local surgery of isolated lesions for palliative intent is acceptable.
• 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 may include clinical history, physical examination and radiographic findings, or tuberculosis 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), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti‑HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Adjust wording as necessary and consider evaluating at screening for studies with known hepatotoxicity or other relevant requirements.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of immunotherapy. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

Eligibility last updated 10/24/22. Questions regarding updates should be directed to the study team contact.