Low Dose Radiation in Combination with Chemo-Immunotherapy for the Treatment of Stage IV Metastatic Lung Non-Small Cell Carcinoma in Previously Untreated Patients, IRRADIATE-Lung Trial

Inclusion Criteria

• Be willing and able to provide written informed consent/assent for the trial
• Pathologically documented, metastatic NSCLC with no previous systemic therapy
• At least 2 distinct measurable metastatic sites, which are 1 cm or larger; patients can have radiation to multiple measurable disease sites as clinically indicated, however, there must be at least 1 measurable non-radiated target lesion for response assessment
• Agreeable to provide archival tissue for correlative studies (1 cell block or 20 slides recommended); if no archival tissue or inadequate number of slides are available, exemption may be granted by the study team. Note: Cytology samples are acceptable
• Be >= 18 years of age on day of signing informed consent
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Have a performance status of =< 2 Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Demonstrate adequate organ function
• Absolute neutrophil count (ANC) >= 1,500/mcL (within 14 days of treatment initiation)
• Platelets >= 100,000/mcL (within 14 days of treatment initiation)
• Hemoglobin >= 7.5 g/dL without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Creatinine clearance =< 3 x upper limit of normal (ULN) OR estimated glomerular filtration rate (eGFR) >= 40 mL/min for subject with creatinine levels > 2 x institutional ULN (within 14 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 2 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT])) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (within 14 days of treatment initiation)
• Albumin > 1.5 g/dL (within 14 days of treatment initiation)
• Have one measurable lesion of at least 1 cm outside the planned radiation field (defined as not receiving direct beam from any of the treatment portals)
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 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 must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Male subjects of childbearing potential must 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 * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

• 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 or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has a known history of active TB (bacillus tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had prior chemotherapy, immunotherapy or targeted small molecule therapy within 6 months prior to study day 1
• Patient who have previously received radiation overlapping, as determined by the treating radiation oncologist, with the current planned radiation treatment fields are ineligible
• Patient's treated with whole brain radiation therapy are ineligible
• 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
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases (with somatostatin receptor scintigraphy [SRS] and/or neurosurgery) may participate provided they are clinically stable and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication
• Patients who have not recovered (i.e., =< grade 2 or at baseline) from adverse events due to a previously administered agent * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting 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 history of autoimmune disorders, (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis
• 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 pre-screening or screening visit through 120 days after the last dose of trial treatment
• Patients with prior history of chemoradiation for lung cancer
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) and with abnormal liver function tests
• 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 [registered trademark]) are live attenuated vaccines, and are not allowed