Chemoradiation Plus Durvalumab Followed by Surgery Followed by Adjuvant Durvalumab in Patients With Surgically Resectable Stage III (N2) Non-Small Cell Lung Cancer

Inclusion Criteria:

* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Age ≥ 18 years at the time of consent.
* ECOG Performance Status of 0 or 1 within 28 days prior to registration.
* Histological or cytological confirmation of NSCLC (Adenocarcinoma, Squamous Cell Carcinoma, Large Cell Carcinoma). A pathology report (from the last 6 months) confirming the diagnosis of NSCLC must be obtained and reviewed by the treating physician prior to registration to study.
* Must have resectable and medically operable stage III (N2) NSCLC with clinical or biopsy-proven N2 disease. If patients have clinical N2 disease they need to be biopsy-proven (with EBUS or mediastinoscopy) during screening and have confirmed prior to study enrollment). Subjects must be considered resectable and medically operable based on the judgment of the treating physician. Stage III (N2) defined as per the 7th edition of the TNM staging system (T1a, T1b, T1c, T2a, T2b, T3, or T4)N2M0.
* Individuals cannot have contralateral neck or contralateral mediastinum nodal involvement.
* Subjects must have a life expectancy of at least 12 weeks to qualify.
* Individuals must not have distant metastasis, defined as M0 in the TMN staging system.
* Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 28 days prior to registration.

  * Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3
  * Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused)
  * Platelets ≥100,000/mcl
  * Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 x upper limit of normal (ULN) OR ≥ 40 mL/min for subjects with creatinine levels \>1.5 x institutional ULN
  * Bilirubin ≤ 1.5 × ULN OR Direct bilirubin of ≤ ULN for subjects with total bilirubin levels of \>1.5x ULN
  * Aspartate aminotransferase (AST) ≤ 2.5 × ULN if no liver metastases

    ≤ 5 x ULN if liver metastases present
  * Alanine aminotransferase (ALT) ≤ 2.5 × ULN if no liver metastases ≤ 5 x ULN if liver metastases present
* All CT or PET imaging studies must be completed within 6 weeks (42 days) prior to registration.
* 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 7 days prior to registration. NOTE: Women are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal. 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 greater than 40 mIU/mL.
* 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 90 days after treatment discontinuation.
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving study drug and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 90 days after the last dose of investigational product.
* 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.

Exclusion Criteria:

* History of a major surgical procedure (as defined by investigator) within 28 days prior to the first dose of study drug. NOTE: Local surgery for isolated lesions for palliative intent is acceptable.
* History of another primary malignancy except for a) malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug, b) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, c) adequately treated carcinoma in situ without evidence of disease.
* History of leptomeningeal disease.
* Persons who have small cell carcinoma.
* Persons who do not meet the Stage IIIA NSCLC classification criteria outlined above.
* Presence of superior vena cava syndrome.
* Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 90 days after the last dose of trial treatment.
* Active central nervous system (CNS) metastases. Subjects must undergo a head computed tomography (CT) scan or brain MRI within 42 days prior to registration for protocol therapy to exclude brain metastases if symptomatic or without prior brain imaging.
* Treatment with any investigational agent within 28 days prior to registration for protocol therapy.
* Patients should not have received any prior therapy for the current diagnosis of NSCLC. Treatments done for previously diagnosed malignancies are permitted. Prior therapy with a PD-1, PD-L1 (including Durvalumab), PD-L2 or CTLA-4 inhibitor or a lung cancer-specific vaccine therapy are not permitted.
* Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be evaluated with a CT or PET scan prior to registration for protocol therapy to exclude metastatic disease.
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:

  * Patients with vitiligo or alopecia
  * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  * Any chronic skin condition that does not require systemic therapy
  * Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  * Patients with celiac disease controlled by diet alone
* Interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

  * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  * Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent
  * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
* History of psychiatric illness or social situations that would limit compliance with study requirements
* Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

  * Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the investigator.
  * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the investigator.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the site investigator.
* Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed. Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. Testing not required.
* Has received a live vaccine within 30 days prior to planned start of study therapy. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
* History of allograft or allogeneic bone marrow transplant.