This phase II trial tests the safety and effectiveness of the combination of grid radiation therapy and standard of care (SOC) immunotherapy in treating patients with stage IV non-small lung cancer (NSCLC). Conventional radiation therapy treatments typically deliver the same radiation dose to the entire tumor. Spatially fractionated radiation therapy or grid therapy is approved and a technique which permits the delivery of high doses of radiation to small regions of the tumor which can lead to enhanced tumor cell killing. Grid therapy has been shown to produce dramatic relief of severe symptoms, significant tumor regression (decrease in the size of a tumor), and above average local control rates often exceeding those expected with conventionally delivered radiation treatments, all with minimal associated toxicity. Immunotherapy has become combined into treating patients, which has led improvements in survival and quality of life. Immunotherapy is now the cornerstone of SOC therapy for stage IV NSCLC. Grid radiation therapy combined with immunotherapy may be safe and effective in treating patients with stage IV NSCLC.

PRIMARY OBJECTIVE:

I. To describe the safety and toxicity of grid + immunotherapy in stage IV NSCLC using any Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

SECONDARY OBJECTIVE:

I. Evaluation of objective response rate using Immune-based Response Evaluation Criteria in Solid Tumors (iRECIST) in non-irradiated lesion(s) after grid therapy in the setting of ongoing immunotherapy.

CORRELATIVE RESEARCH:

I. Monitoring of peripheral blood T cell activation and immunity markers before and after grid therapy.

II. Evaluation of objective response rate using RECIST in the irradiated lesion after grid therapy.

III. Evaluation of time to change in systemic therapy. IV. Evaluation of overall survival.

OUTLINE:

Patients undergo grid radiation therapy over a single fraction on day 1 and palliative radiation therapy over 5 fractions on days 2 and -1 post-grid in the absence of disease progression or unacceptable toxicity. Patients also receive SOC immunotherapy and undergo computed tomography (CT) at the discretion of the physician and undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days then every 8-12 weeks and every 3 months up to 5 years.

Inclusion Criteria:

• Age ≥ 18 years

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

• Stage IV non-small cell lung cancer progressing after immunotherapy or chemoimmunotherapy

• Extracranial lesion ≥ 3 cm amenable to grid therapy

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

    • They are stable (without evidence of progression by imaging ≤ 30 days prior 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 or stereotactic body radiotherapy (SBRT) to other metastatic sites (provided there is at least one non-irradiated lesion evaluable for response)

• Negative pregnancy test done ≤ 7 days prior to radiation therapy for females of childbearing potential only

• Provide written informed consent

• Willing to provide mandatory blood specimens for correlative research

• Willing to either return to Mayo Clinic for follow-up (during the Active Monitoring Phase of the study) or willing to have virtual visits and blood draws done locally

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

Exclusion Criteria:

• 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
    • 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] surface antigen [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 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

• 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

• 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