Nivolumab in Treating Patients With Stage IV or Recurrent Lung Cancer With High Mutation Loads

Inclusion Criteria:

* • Signed written informed consent

  * Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care
  * Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing

    * Eastern Cooperative Oncology Group (ECOG) performance status of =\< 1
    * Subjects with histologically confirmed stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification squamous or nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease
  * Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration is at least 2 months prior to enrollment
  * Prior definitive chemoradiation for locally advanced disease is also permitted as long as the last administration of chemotherapy or radiotherapy (whichever was given last) occurred at least 2 months prior to enrollment

    * Mutation load determined by FoundationOne of \>= 20 mutations/MB tested on archival tumor sample; the mutation load metric will be displayed on the FoundationOne report for all participating sites as "tumor mutation burden (TMB) - high" or may be obtained from Foundation Medicine from older reports using the Insights Portal, which will be available to all participating sites, or by emailing Foundation Medicine
    * Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria
  * Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy

    * Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been completed at least 2 weeks prior to enrollment; subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of enrollment are strongly encouraged to receive palliative radiotherapy prior to enrollment
    * White blood cell (WBC) \> 2000/uL
    * Neutrophils \> 1500/uL
    * Platelets \> 100 x 10\^9/uL
    * Hemoglobin \> 9.0 g/dL
    * Serum creatinine =\< 2 x upper limit normal (ULN) or creatinine clearance (CrCl) \>= 30 mL/min using the Cockcroft-Gault formula
    * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3 x ULN (unless liver metastases, who can have AST/ALT =\< 5 x ULN)
    * Total bilirubin =\< 3 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin \< 3.0 mg/dL)
    * Women must not be breastfeeding
    * Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of nivolumab
  * "Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
  * Menopause is defined as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; if menopausal status is considered for the purpose of evaluating childbearing potential, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level \> 40 mIU/mL, in order to be considered postmenopausal and not of childbearing potential

    • Women of child bearing potential (WOCBP) and men able to father children who are sexually active with WOCBP must agree to use acceptable contraception
  * Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception
  * Women of childbearing potential receiving nivolumab will be instructed to use and must be willing to use appropriate method(s) of contraception for a period of 23 weeks after the last dose of investigational product
  * Men receiving nivolumab who are sexually active with WOCBP will be instructed to use and must be willing to use acceptable contraception for a period of 31 weeks after the last dose of investigational product

Exclusion Criteria:

* Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 \[L858R\] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged
* Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded; if tested, use of an FDA-approved test is strongly encouraged; subjects with unknown or indeterminate ALK status may be enrolled
* Active brain metastases or leptomeningeal metastases (carcinomatous meningitis); subjects with brain metastases are eligible if these have been treated and there is no evidence of progression for at least 2 weeks after treatment is complete and corticosteroid dose is stable (and equivalent dose of \< 10 mg prednisone) for at least 2 weeks
* Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before enrollment
* Subjects with an active, known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first study treatment with nivolumab; inhaled or topical steroids, and adrenal replacement steroid \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
* Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection)
* Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
* Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration
* Subjects with previous or active malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to enrollment and no additional therapy is required or anticipated to be required during the study period
* History of allergy to study drug components or of severe hypersensitivity reaction to any monoclonal antibody
* Prisoners or subjects who are involuntarily incarcerated
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness