Platinum Doublet in Combination with Nivolumab followed by Surgery or Concurrent Chemoradiation for the Treatment of Unresectable Stage IIIA-C Non-Small Cell Lung Cancer

Inclusion Criteria

• Squamous and non-squamous non-small cell lung cancer that is at baseline, unresectable stage IIIA-IIIC (8th edition American Joint Committee on Cancer [AJCC]) and not previously treated. Patients will have a treatment plan for definitive chemotherapy-radiation. Measurable disease as defined by RECIST * For any eligible patient, the primary tumor must be resectable at baseline T1-T4 (resectable T4). Thus, unresectability is on the basis of the lymph nodes * Baseline histologic or cytologic confirmation and/or imaging determined nodal involvement is outlined below. Tissue confirmation of all mediastinal nodal involvement is not required, however at least one N2 or N3 lymph node needs to be positive. If only 1 N2 lymph node station is positive, patients can still be eligible if other mediastinal N2 lymph node stations or N3 nodal involvement can be declared by imaging when the nodes have distinct margins and the size of the shortest axis of one such lymph node is at least 1 node is >= 2.0 cm (MRI/CT scan) If a single N3 lymph node is biopsy positive, any T stage is permissible as long as the primary is resectable. No other pathologic or radiographic evidence of lymph node involvement is required if the N3 is biopsy positive * IIIA is eligible if the primary, T1-T2, is technically resectable at baseline and is unresectable on the basis of: ** N2 with 2 or more ipsilateral lymph node stations involved * IIIB is eligible if the primary is technically resectable at baseline but is unresectable on the basis of: ** N2 with 2 or more ipsilateral lymph node stations involved (and T3 or T4 status) OR ** N3 (including contralateral mediastinal, contralateral hilar, or supraclavicular) with T1- T2 status. Patients can have baseline bulky bilateral mediastinal lymph nodes and supraclavicular lymph nodes and be eligible * IIIC is eligible if the primary, T3- T4, is technically resectable at baseline but is unresectable on the basis of: ** N3 (including contralateral mediastinal, contralateral hilar, or supraclavicular) patients can have baseline bulky bilateral mediastinal lymph nodes and supraclavicular lymph nodes and be eligible
• PD-L1 level needs to be measured with values 0-100% eligible
• EGFR/ALK/ROS1 wild type or unknown genetic alterations in these genes
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 100, 000/mcL
• Hemoglobin >= 9.0 g/dL
• Measured or calculated creatinine clearance (Cockcroft-Gault formula) >= 45 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN )
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN
• Adequate pulmonary reserve (e.g., forced vital capacity [FVC], forced expiratory volume in 1 second [FEV]1, total lung capacity [TLC], functional residual capacity [FRC], and diffusion capacity of the lung for carbon monoxide [DLCO]) capable of tolerating the proposed lung resection according to the surgeon and must also be capable of tolerating definitive chemotherapy-radiation therapy with a minimum pulmonary function (PFT) as follows: * Has adequate PFT defined as a FEV1 > 50% of predicted normal volume and the carbon monoxide lung diffusing capacity (DLCO) > 40% of predicted normal value. Participants for whom DLCO measurements are not available will be deemed to have adequate oxygen transfer if pulse oximetry (oxygen [O2] saturation) is determined to be >= 90% on room air
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• The effects of systemic chemotherapy and nivolumab on the developing human fetus are unknown. For this reason and because systemic chemotherapy and nivolumab agents as well as other therapeutic agents used in this trial are known to be teratogenic, women who are pregnant or lactating are excluded from this trial. Additionally, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 5 months after completion of nivolumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of nivolumab administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients who have participated in a study with an investigational agent or device within 2 weeks of enrollment
• Any prior radiotherapy to the lung
• Any prior treatment for the current non-small cell lung cancer (NSCLC)
• Any prior therapy with anti-PD-1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Any history of a severe hypersensitivity reaction to any monoclonal antibody
• Any history of allergy to the study drug components
• Patients cannot have a pancoast tumors whether T3 or T4 by 8th edition lung cancer stage classification
• Patients cannot have primary tumors involving the esophagus
• Patients cannot have primary tumors which would remain unresectable even if an excellent response since this study obliges a complete resection of the primary tumor even if post-induction evaluation indicate potential pCR. An example would be tumors enveloping unresectable large blood vessels. However, since there is not an obligation to resect lymph nodes which on evaluation appear to have a pCR, such lymph nodes seen at baseline are not a barrier to study enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or other agents used in study
• Any active or history of autoimmune disease (including any history of inflammatory bowel disease), or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
• Ongoing requirement for systemic corticosteroids greater than the equivalent of prednisone 10mg. However, inhalational steroids are allowed
• Subjects with previous malignancies are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period * Exceptions to this exclusion are: non-melanoma skin cancers, in situ bladder, gastric, breast, colon or cervical cancers/dysplasia
• Subjects with a history of interstitial lung disease
• Patients requiring continuous supplemental oxygen are excluded
• Use of any live vaccines against infectious diseases (e.g., nasal influenza, varicella. etc.) within 4 weeks (28 days) of initiation of study therapy
• Active systemic infection requiring therapy
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements