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

Inclusion Criteria:

Patients must have histologically confirmed, locally advanced or metastatic stage IV or non-resectable stage III non-small cell lung cancer (NSCLC)
Patients may have received any number and type of prior treatment regimens for their NSCLC (aside from patients in arm A, who cannot have had PD-1/PD-L1 inhibitors)

Arm A: patients must be treatment naive to single agent PD-1/PD-L1 inhibitors including but not limited to durvalumab, pembrolizumab, atezolizumab, nivolumab, and avelumab

Arm B: patients' tumor must be either refractory to or progressed on one of the above agents
Both cases are defined by initial progressive disease (PD) or PD after CR, PR, or SD using RECIST criteria, respectively

Patients must have measurable disease according to the standard RECIST version 1.1

NOTE: computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess the measurable disease must have been completed with 28 days prior to the study drug initiation
Patients need to have adequate kidney, bone marrow, and liver functions =< 14 days of registration as specified below:
Absolute neutrophil >= 1,000/mcL; transfusion and/or growth factor are permitted within any timeframe
Platelets >= 50,000/mcl; transfusion and/or growth factor are permitted within any timeframe
Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (or =< 3 times ULN in case of liver metastasis or Gilbert syndrome)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 2.5 X institutional ULN (or =< 5 times ULN in case of liver metastasis)
Creatinine =< 1.4 ng/mL for females; =< 1.5 ng/mL for males; patients with creatinine =< 2.0 ng/mL may still be eligible if in the opinion of the investigator, the benefits of treatment outweigh the risks
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

Females of child-bearing potential (FOCBP) and men who are sexually active must agree to follow instructions for method(s) of contraception for the duration of treatment and the designated post-treatment period

NOTE: a FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy
Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
FOCBP must have a negative pregnancy test =< 7 days prior to registration on study

Patients with known history of central nervous system (CNS) metastases are eligible if CNS disease has been radiographically and neurologically stable for at least 6 weeks prior to study registration and do not require corticosteroids (of any dose) for symptomatic management

NOTE: CNS imaging is only required at baseline for patients with known history of CNS metastases
Patients must have the ability to swallow oral medications

Patients who are known to be EGFR- or ALK-positive must have received prior EGFR- or ALK-targeted therapy, respectively

NOTE: in such cases, documentation of EGFR mutation or ALK translocation status should be provided if available

Exclusion Criteria:

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

Arm B: patients who were on metformin while on PD-1/PD-L1 inhibitors are not eligible

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

Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:

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