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

Eligibility Criteria

• * Age \>= 18 years at time of informed consent
• * • Histologically documented or cytologically confirmed diagnosis of stage IVA or IVB (M1b or M1c) or locally advanced (not eligible for standard of care \[SOC\] chemoradiation) 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 to receive therapy as determined by investigators and other treating physicians
• * Participants with brain metastases that can be comprehensively managed with surgery and/or stereotactic radiosurgery, prior to initiation of chemo-immunotherapy are allowed. Number of brain metastases allowed is not specified at eligibility is at discretion of investigator
• * 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
• * 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
• * Brain metastases that would require administration of whole brain radiotherapy for management on required screening brain MRI within 21 days of day 1 of study treatment
• * Symptomatic malignant ascites or malignant pleural effusion (sampling not required). Pleural metastases are allowed if deemed targetable with radiotherapy
• * 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 \>1 cycle of immune checkpoint inhibitor for current malignancy (prior cytotoxic chemotherapy is allowed)
• * 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