The purpose of this study is to closely examine tumor and blood samples from patients treated with nivolumab and ipilimumab in order to try to identify why some patients with lung cancers respond and why some patients do not.

Inclusion Criteria:

• Patient must be capable, willing, and able to provide written, informed consent.

• ≥ 18 years old.

• Advanced stage NSCLC

• Previously treated with no more than two lines of prior systemic therapy for advanced stage lung cancer.

  • Patients who previously received neoadjuvant, concurrent, or adjuvant chemotherapy for localized NSCLC and then recurred within 6 months of completing chemotherapy may be considered as having received one line of prior therapy
  • Maintenance therapy does not count as a separate line of therapy

• Patients must:

  • Be scheduled to undergo a standard-of-care resection of tumor tissue as part of treatment plan prior to beginning study therapy. Patients may not have intervening systemic anti-cancer therapy between the time of resection and treatment with nivolumab.
  • Have collection of adequate pre-treatment tissue for correlative analysis defined as sufficient material for 1) frozen tissue for DNA/RNA with touch prep/representative slide confirming tumor material present, 2) FFPE material for ICH with touch prep/representative slide confirming tumor material present, and 3) single-cell suspensions with >20 million live cells after tissue digestion but before freezing. Adequacy of collected material will be determined within 5 business days of each collected case.
  • Have residual disease following surgical resection that is measurable by RECIST v1.1
  • Previously irradiated sites of tumor may be considered measurable if there is radiographic progression at that site subsequent to the time of completing radiation.
  • Have a safely biopsiable tumor lesion

• ECOG performance status of 0-1.

• Adequate hematologic, renal, and/or hepatic function (following criteria must be met within 28 days of C1D1:

  • WBC ≥ 2,000/ul
  • ANC ≥ 1,500/ul
  • Hemoglobin ≥ 9.0 g/dl
  • Platelet count ≥ 100,000/ul
  • Total bilirubin ≤ 1.5 x ULN (unless evidence of Gilbert's syndrome, in which case, direct bilirubin must be ≤ 1.0 x ULN)
  • AST and ALT ≤ 3 x UNL (unless elevated transaminases are felt to be directly related to metastatic disease involving the liver, in which case AST and ALT must be ≤ 5x ULN)
  • Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance of ≥ 40 mL/min calculated using the formula of Cockcroft and Gault: (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female

• There is no restriction on the number of prior lines of systemic anti-cancer therapy. For those who have received prior systemic anti-cancer therapy, there must be at least 3 weeks since last systemic therapy.

• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 3 days prior to the start of study drug.

• Effective contraception:

  • Women of childbearing potential must agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 23 weeks (5 half-lifes plus 30 days, the duration of an ovulatory cycle) after the last dose of nivolumab, or agree to completely abstain from heterosexual intercourse.
  • Male subjects, even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through 31 weeks (5 half-lives plus 90 days, the duration of sperm turnover) after the last dose of study drug, or completely abstain from heterosexual intercourse.

Exclusion Criteria:

• Patients who are pregnant or lactating.

• Presence of activating EGFR mutations or ALK re-arrangement,unless previously treated with standard TKI therapy. All patients with adenocarcinoma histology must be tested for EGFR and ALK status.

• History of allergy to study drug components or history of severe hypersensitivity reaction of any monoclonal antibody.

• Prior treatment with immune checkpoint inhibitor, including (but not limited to) those targeting PD-1, PD-L1, PD-L2, CTLA-4, CD137, GITR, TIM3, LAG3, or OX40

• Any systemic anti-cancer therapy within 3 weeks prior to C1D1 of study therapy

• Exception is made for patients with EGFR or ALK re-arrangements who must have stopped TKI therapy at least 7 days prior to C1D1

• Patients who have not previously been treated with platinum-based based doublet chemotherapy and who, in the judgment of the investigator, have rapidly progressive disease such that serious complications may arise from disease progression within the next 12 weeks will be excluded.

• Non-CNS radiotherapy within 1 week prior to C1D1 of study therapy

• Active infection requiring therapy

• Prior systemic immunosuppressive therapy (> 10 mg/day prednisone equivalents) within 1 week prior to C1D1 of study therapy. Inhaled, ocular, intra-articular, intranasal, and topical corticosteroids are permitted in absence of active autoimmune disease.

  • Adrenal replacement doses are permitted in the absence of active autoimmune disease.

• Patients with known or suspected history of autoimmune disease. Subjects with type I diabetes melitis, hypothyroidism only requiring hormone replacement, resolved childhood asthma/atopy, patients with asthma requiring intermittent bronchodilator therapy, 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.

• Other active malignancy requiring concurrent intervention.

• Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless definitive therapy has been completed at least 1 year prior to study entry and the patient is now without evidence of disease from that malignance and no additional therapy is required or anticipated to be required during the study period.

• Known untreated brain or leptomeningeal metastasis.

  o Patients with brain metastases are eligible if metastases have been adequately treated and neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least two weeks prior to C1D1. In addition, 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.

• Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.

• Any positive test for HIV

• Any positive test for HCV RNA or HBsAg.

48 weeks