University of Texas Medical Branch

Subject must meet all of the following applicable inclusion criteria to participate in this study: 1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 2. Age ≥ 18 years at the time of consent. 3. ECOG Performance Status of 0-2 within 28 days prior to randomization. 4. Histological or cytological confirmed squamous or non-squamous non-small cell lung cancer. 5. Measurable disease according to RECIST 1.1 within 28 days prior to randomization. 6. A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to randomization, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. 7. Subjects must have primary resistance to PD-1 or PDL-1 inhibitors; defined as PD after 3 or fewer treatments with a PD-1 or PDL-1 inhibitor 8. Subjects must have progressed on or after previous platinum-based chemotherapy. Chemotherapy may have previously been given with a PD-1 or PD-L1 inhibitor. Subjects must have also progressed on or after receiving any PD-1 or PD-L1 inhibitor (including nivolumab) as their most recent therapy. 9. Most recent PD-1 or PD-L1 inhibitor infusion must be completed at least 6 weeks of randomization. The subject must have recovered from all reversible acute toxic effects (other than alopecia) to ≤ Grade 1 or baseline. 10. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to randomization. White blood cell (WBC) ≥ 2 k/mm3 Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3 Hemoglobin (Hgb) ≥ 9 g/dL Platelet >100k Estimated creatinine clearance OR ≥ 40 cc/min Serum creatinine ≤ 1.5 x upper limit of normal (ULN) Bilirubin 1.5 ≤ (ULN)2 Aspartate aminotransferase (AST) ≤ 1.5 × ULN Alanine aminotransferase (ALT) ≤ 1.5 × ULN International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 2 × ULN (Note: use of vitamin K antagonist is not allowed) 11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to registration. These women must also have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab then every 6 weeks thereafter. NOTE: Women are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are post-menopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. 12. Women of childbearing potential must be willing to abstain from heterosexual activity or use an effective method of contraception from the time of informed consent until 5 months after treatment discontinuation. Women cannot breast feed from the time of informed consent to 5 months after last dose of study treatment. See below for adequate methods of contraception. 13. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. See below for methods of contraception. 14. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

1. Prior treatment with the single agent chemotherapy the site investigator chooses to use for this protocol (pemetrexed, taxotere or gemcitabine). 2. Previous autoimmune complication from PD-1 or PD-L1 requiring discontinuation of therapy or treatment with steroids (ongoing treatment with more than 10 mg of prednisone or steroid equivalent daily, excluding inhaled or topical steroids). 3. Previous discontinuation from PD-1 or PD-L1 due to an adverse event. 4. Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy. 5. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). 6. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. 7. Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for [lowest minimum is 4 weeks or more] after treatment is complete and within 28 days prior to the first dose of Nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. 8. Treatment with any investigational drug within 30 days prior to registration. 9. Subjects whose tumors express EGFR mutations on exons 19 and 21, ALK rearrangement, or ROS1 rearrangement who still have other FDA approved targeted agents available for treatment. 10. Subjects with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with vitiligo, autoimmune thyroiditis, or type I diabetes mellitus are permitted to enroll.) 11. As there is potential for hepatic toxicity with Nivolumab, drugs with a predisposition to hepatoxicity should be used with caution in subjects treated with Nivolumab-containing regimen. 12. Subjects should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 13. Subjects should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 14. History of allergy to study drug components. 15. Prior solid organ or stem cell transplant