Nivolumab and Metformin Hydrochloride in Treating Patients With Stage III-IV Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

Both arms: patients should not have received metformin within 6 months prior to registration

Patients should not have received prior immunotherapies (exception; arm B); they include but are not limited to interleukin-2 and other immune checkpoint antagonist targeting CTLA-4, LAG-3, TIM-3, KIR etc. and/or agonists targeting OX40, ICOS, CD137, etc

* NOTE: prior cancer vaccine treatments are permitted; for arm B, exposure to single agent PD-1/PD-L1 inhibitors are allowed \>= 14 days from registration

Arm B: patients must not have had prior exposure to combination treatment with PD-1/PD-L1 inhibitors and another systemic treatment

* NOTE: radiation therapy and surgery do not count as combination treatment

Patients who are intolerant to PD-1/PD-L1 inhibitors and/or metformin are excluded

Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of:

* Immune related neurologic disease

* Multiple sclerosis

* Autoimmune (demyelinating) neuropathy

* Guillain-Barre syndrome

* Myasthenia gravis

* Systemic autoimmune disease such as systemic lupus erythematosus (SLE)

* Connective tissue diseases

* Scleroderma

* Inflammatory bowel disease (IBD)

* Crohn's

* Ulcerative colitis

* Patients with a history of toxic epidermal necrolysis (TEN)

* Stevens-Johnson syndrome

* Anti-phospholipid syndrome

* NOTE: subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll

Patients are ineligible who have any condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications =\< 14 days prior to registration

* NOTE: inhaled steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; a brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted

* Uncontrolled hypertension - blood pressure \>= 150/90 mmHg despite medical therapy

* Ongoing or active infection requiring systemic treatment

* Symptomatic congestive heart failure

* Unstable angina pectoris

* Cardiac arrhythmia

* Psychiatric illness/social situations that would limit compliance with study requirements

* Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints

Patients must not have had another primary malignancy within 2 years prior to starting study treatment with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix, or any local cancers that are deemed to be cured from investigator's point of view

Patients may not be receiving any other investigational agents =\< 14 days from registration

Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are excluded

Patients who have any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection are excluded

Patients with known diabetes whose glucose control or general health condition may be adversely affected by the use of metformin as per the study protocol as deemed by either the study investigator or endocrinologist are excluded

Patients must not have any of the following contraindications to metformin:

* Hypersensitivity to metformin or any component of the formulation

* Kidney dysfunction or abnormal creatinine (Cr \< 2 ng/mL) from any cause

* Acute or metabolic acidosis

What this study is about