Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

Inclusion Criteria:

* Histologically or cytologically-proven non squamous cell NSCLC; mixed histology with small cell lung carcinoma (SCLC) component not allowed
* Patients with stage II ? IV non squamous cell NSCLC who received at least 54 Gy of total planned thoracic radiation dose will be eligible; patients must have received at least one cycle of chemotherapy concurrently during the course of thoracic radiation; regimens allowed are platinum combinations with either etoposide or a taxane regardless of histology subtype; platinum with pemetrexed for patients with non-squamous NSCLC only; patients with oligometastatic stage IV cancer are eligible if they have received only one line of systemic therapy for their stage IV cancer prior to the concurrent chemoradiation phase
* Patient must have had a complete response (CR)/partial response (PR)/stable disease (SD), 4-6 weeks after completing last fraction of radiation therapy
* Eastern Cooperative Oncology Group (ECOG) performance score 0-2
* Absolute neutrophil count (ANC) \>= 1,500/uL
* Platelet count \>= 100,000/uL
* Hemoglobin \>= 9 g/dL
* Total bilirubin =\< normal or for those with Gilbert?s syndrome =\< 1.5 times upper limit of normal (ULN) OR direct bilirubin normal (per institute standards)
* Aspartate aminotransferase (AST) =\< 1.5 x ULN; alanine aminotransferase (ALT) and AST =\< 2.5 x ULN is acceptable if there is liver metastasis
* Fertile patients must use adequate contraception

Exclusion Criteria:

* Whole-brain radiotherapy (WBRT) \< 14 days from the anticipated start of nintedanib/placebo administration
* Squamous cell NSCLC
* Unable to start nintedanib/placebo treatment between 4-8 weeks after completing the last dose of thoracic radiation
* Active untreated brain or leptomeningeal metastases; in patients with treated central nervous system (CNS) metastases, eligible if symptoms controlled for at least 4 weeks; dexamethasone allowed if total daily dose does not exceed 2 mg
* Major injuries or surgery (e.g., craniotomy) \< 28 days from the start of nintedanib/placebo administration; wound should be healed prior to starting therapy
* Second malignancies are allowed as long as the disease does not require active treatment with concomitant systemic cytotoxic chemotherapy, investigational or biologic therapy (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 \[CTLA4\] or human epidermal growth factor receptor 2 \[HER2\] monoclonal antibodies); hormone-related therapies (e.g., gonadotrophin releasing hormone (LHRH) agonists, tamoxifen, etc.) are allowed
* Concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would increase the risk associated with study participation and/or limit compliance with study requirements
* Inability to swallow study medication
* Presence of active malabsorption disorder (e.g., flare episodes documented within the preceding 3 months, presence of symptoms requiring daily medications for control) or history of extensive small bowel resection
* Known bleeding or thrombotic diathesis
* History of arterial or venous thromboembolic event within 12 months prior to study participation
* Active hemoptysis or history of clinically relevant hemoptysis as determined by the treating physician; patients who had history of transient minor hemoptysis after bronchoscopic biopsy are eligible unless deemed otherwise by the treating physician
* Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher proteinuria
* Investigational agent administered \< 28 days prior to treatment with nintedanib. Last dose of systemic chemotherapy administered \< 14 days prior to treatment with nintedanib
* Known chronic active hepatitis B or hepatitis C; human immunodeficiency virus (HIV)-positive patients receiving or are candidates for antiretroviral therapy are also excluded
* Pregnancy or breast feeding; female patients with child-bearing potential must have a negative pregnancy test (beta-human chorionic gonadotropin \[B-HCG\] test in urine or serum) prior to commencing study treatment
* Creatinine \> 1.5 x ULN or creatinine clearance levels (CrCL) \< 45 mL/min
* Centrally located tumors with radiographic evidence (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) of local invasion of major blood vessels
* Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid \< 325 mg per day)
* Active or previous autoimmune disease requiring treatment within the past 2 years will exclude patients from receiving immune checkpoint inhibitor in this study. Exception allowed: endocrine conditions treated with necessary hormone replacement or other supportive medication; vitiligo, alopecia