Atezolizumab and Varlilumab in Combination With Radiation Therapy for NSCLC

Inclusion Criteria:

* Must have signed and dated written informed consent form in accordance with regulatory and institutional guidelines
* Histological or cytological evidence of advanced, unresectable NSCLC
* Patients must be PD-1/PD-L1 experienced with disease progression documented either on therapy with anti-PD-1/PD-L1 or within 12 weeks of the last dose. Treatment should be initiated at least 4 weeks since last dose of PD-1/PD-L1 targeted therapy
* Patients must have progressed on at least one line of prior platinum-based chemotherapy in the metastatic setting. Subjects with unresectable stage III NSCLC who received platinum-based chemotherapy as part of chemoradiation or consolidation chemotherapy after chemoradiation are eligible if they progress within 6 months of last dose of chemotherapy. Treatment should be initiated at least 4 weeks since last dose of systemic therapy
* Subjects with an actionable molecular alteration (such as EGFR mutation, ALK or ROS1 rearrangement, BRAF V600E mutation) are eligible only after failing standard-of-care targeted therapy with tyrosine kinase inhibitor (TKI). Patients with a EGFR T790M resistant mutation must have failed a 3rd generation TKI such as osimertinib
* Must not have received any prior therapy with immune regulatory molecule (such as targeting OX-40, IDO-1, LAG-3) or anti-CD27 monoclonal antibody (including varlilumab)
* Must have at least one lesion that has not previously been irradiated (and is not within a previously radiated field) and for which palliative radiation is potentially indicated. The lesion to be irradiated must be in the lung. Patient must have at least one additional measurable lesion (other than the lesion being radiated) as per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria. Patient must agree to undergo a mandatory biopsy of the non-irradiated lesion pre-treatment and post-treatment (after cycle 2). Pre-treatment tissue obtained by biopsy or resection performed according to standard of care may be utilized, provided tissue was obtained within 8 weeks of study entry, and subsequent to the last systemic anticancer therapy received
* Patients should have fewer than 10 metastatic sites and expected survival of more than 3 months
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Treatment to be initiated at least 2 weeks since last dose of prior systemic anticancer therapy (chemotherapy, radiation, and/or surgery)
* Recovery to grade 1 of any clinically significant toxicity (excluding alopecia, grade 2 fatigue, vitiligo, endocrinopathies on stable replacement therapy, grade 2 neuropathy from chemotherapy and grade 2 hearing loss from platinum chemotherapy) prior to initiation of study drugs
* Female patients of childbearing potential have a negative pregnancy test at baseline. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression

  * Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within 14 days of treatment initiation
  * Sexually active women of childbearing potential enrolled in the study must agree to use 2 forms of accepted methods of contraception during the course of the study and for 12 weeks after their last dose of study drug. Effective birth control includes (a) intrauterine device plus 1 barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner
  * For male patients who are sexually active and who are partners of premenopausal women: agreement to use 2 forms of contraception as in criterion above during the treatment period and for 12 weeks after the last dose of study drug
* Absolute neutrophil count \>= 1,500/uL
* Platelet count \>= 100,000/uL
* Hemoglobin \>= 9.0 g/dL
* Total bilirubin =\< 2 x upper limit of normal (ULN) or =\< 3 x ULN for subjects with Gilbert?s disease or liver metastases
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN (=\< 5 x ULN if evidence of hepatic involvement by malignant disease)
* Creatinine =\< 1.5 x ULN or estimated glomerular filtration rate (eGFR) \>= 40 mL/min/1.73m\^2
* Measurable disease according to irRECIST obtained by imaging within 28 days prior to treatment initiation

Exclusion Criteria:

* 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 23 weeks (female) or 31 weeks (male) after the last dose of study drug
* Treatment with any investigational agent within 28 days prior to registration for protocol therapy
* History of psychiatric illness or social situations that would limit compliance with study requirements. 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
* Known active, untreated central nervous system (CNS) metastases and/or carcinomatous meningitis except for patients with =\< 3 small (\< 0.6 cm) asymptomatic brain lesions where treatment is not indicated. Patients with neurological symptoms must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images obtained after treatment to the brain metastases at least 4 weeks apart and show no evidence of intracranial progression)
* Known history of human immunodeficiency virus (HIV) or active hepatitis B (by surface antigen expression or polymerase chain reaction \[PCR\]) or active hepatitis C (by PCR) infection
* Diagnosis of immunodeficiency or is receiving systemic steroid therapy (\> 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to study registration
* 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) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Vitiligo, alopecia, hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, celiac disease controlled by diet alone or conditions not expected to recur in the absence of an external trigger are permitted
* Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) class III?IV within 6 months prior to their first dose of study drugs
* Prior malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 1 year prior to study entry
* Any active grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drugs. Routine antimicrobial prophylaxis is permitted
* Active diverticulitis
* History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted