Split Course Adaptive Radiation Therapy With Pembrolizumab With/Without Chemotherapy for Treating Stage IV Lung Cancer

Inclusion Criteria:

Age >= 18 years at time of informed consent
Histologically documented or cytologically confirmed diagnosis of stage IVA or IVB (M1b or M1c) non-small cell lung cancer with evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria
Available tumor material (< 6 months old) adequate for confirmation of programmed cell death 1 ligand 1 (PD-L1) expression per local standard of care testing
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Adequate organ function defined by following laboratory values:

Hematologic: ANC ≥ 1.5 x 109 /L, platelet count ≥ 100 x 109 /L, and hemoglobin ≥9 g/dL
Adequate hepatic function defined by total bilirubin ≤1.5 x upper limit of normal (ULN), AST ≤ 3.0 x ULN, ALT ≤ 3.0 x ULN and alkaline phosphatase ≤ 2.5 x ULN
Adequate renal function defined by creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min if Cr > 1.5 x ULN. GFR can also be utilized. If no local calculation guidance on CrCl, should be calculated according to Cockcroft-Gault Method.
Adequate coagulation function defined as international normalized ration (INR) or prothrombin time (PT) ≤ 1.5 x ULN and activate partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulation therapy.
No prior systemic therapy for advanced/metastatic non-small cell lung cancer (NSCLC) (prior adjuvant chemotherapy following complete resection of early-stage NSCLC I-II is allowed)
Participants with 5 or fewer brain metastases are eligible if intracranial sites can be treated with surgery and/or stereotactic radiosurgery, prior to initiation of chemo-immunotherapy
Contraceptive use should be initiated or continued per guidance in labeling for approved chemotherapies

Female patients must be non-pregnant and not breastfeeding.

If woman of childbearing potential (WOCBP), must utilize highly effective contraceptive method (failure rate of < 1% per year) throughout intervention period and continued per guidance specified in labeling for approved chemotherapies. Must have negative pregnancy test (serum or urine) within 1 week prior to initiation of first cycle of therapy
Eligible for immunotherapy-based systemic regimens per judgment of patient's study physician
Able to submit written informed consent

Exclusion Criteria:

Mixed small cell histology
Confirmed candidate (per study physician) for alternative systemic therapy if preferred by treating physician (i.e. mEGFR, ALK, KRAS G12C or ROS1 mutations). Testing not required for enrollment
Greater than 5 brain metastases on required screening brain magnetic resonance imaging (MRI) within 21 days of day 1 of study treatment
Symptomatic ascites or malignant pleural effusion (sampling not required)
Major surgery (requiring general anesthesia or at discretion of study physician) within 4 weeks prior to study enrollment that would prevent treatment with SiCARIO regimen
History of organ transplant requiring therapeutic immunosuppression
Known clinically significant (per study physician) acute or chronic infections including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or active tuberculosis (testing not required). Patients with HBV and HCV must be on stable dose of antiviral therapy on study entry
Uncontrolled intercurrent illness including, but not limited to, New York Heart Association (NYHA) class III-IV congestive heart failure, uncontrolled hypertension (average systolic blood pressure greater than or equal to 140 or average diastolic blood pressure greater than or equal to 90 despite optimal medical therapy), unstable angina pectoris, cardiac arrythmia, active peptic ulcer disease, bleeding diatheses or psychiatric illness that would limit in the judgment of the study physician
Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 30 days of day 1 of study treatment
History of prior independent malignancy within 3 years of enrollment, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ (e.g. cervix or non-invasive bladder cancer)
Receipt of prior cytotoxic chemotherapy or anti-neoplastic biologic/immunotherapy for current malignancy (prior adjuvant therapy for completely resected early stage NSCLC that has now recurred in metastatic state is permissible)
Prior radiotherapy that would preclude delivery of protocol- based radiotherapy to normal organ tolerance per patient's study physician
Current or prior use of immunosuppressive medications within 28 days of enrollment with exception of intranasal or inhaled corticosteroids or systemic steroids at physiologic doses (equivalent to less than or equal to 10 mg/day of prednisone). Systemic steroids required during therapy for adverse event (AE) management and for residual neurologic complications from management of central nervous system (CNS) metastases are allowed at doses exceeding 10 mg/day of prednisone equivalents
Active autoimmune disease requiring systemic treatment within past 1 year
Receipt of live attenuated vaccine within 30 days of enrollment
Use of prohibited concomitant drug within 30 days of enrollment
Known severe (>= grade 3 Common Terminology Criteria for Adverse Events [CTCAE]) hypersensitivity to study intervention or formulation
Concurrent enrollment in another clinical trial (unless observational or within follow-up period)
Any condition at discretion of investigator that will preclude participation in the study