Operability Criteria:
1. ECOG Performance Status 0-1.
2. Absence of major associated comorbidities that increase the surgery risk to an unacceptable level.
3. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1 at least 2 L. If less than 2 L, the predicted postoperative forced expiratory volume in 1 second (FEV1) must be \>0.8 L or be \>35% of the predicted value. Postoperative predicted DLCO ≥35% is required.
Inclusion Criteria:
1. Patients who are at least 18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
3. Life expectancy of at least 12 weeks.
4. Patients with potentially resectable IIIA/B (T1-3, N2) NSCLC (per the 8th International Association for the Study of Lung Cancer classification) who are candidates for surgery with intent of R0 resection. Invasive T3 disease (eg, phrenic nerve, pericardium, chest wall other than Pancoast superior sulcus) may be included if the surgeon and study team deem it to be resectable. T4 disease per AJCC 8th edition staging system is excluded given the lack of benefit of surgery in T4N2.
5. Patients must be evaluated by a thoracic surgeon within 4 weeks of registration.
6. Operability is defined as having adequate pulmonary, cardiac, renal, nutritional, musculoskeletal, neurologic, and cognitive capacity to undergo major pulmonary resection with acceptable morbidity and mortality.
7. N2 nodes must be discrete (ie, not invading surrounding structures) and less than 3 cm in maximum diameter.
8. Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
9. Pathologically proven N2 disease within 4 weeks of registration. PET/CT positivity in the ipsilateral mediastinal nodes will not be sufficient to establish N2 nodal status. Mediastinal lymph node sampling biopsy is required pre-operatively by at least one of the following:
* Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA);
* Mediastinoscopy;
* Mediastinotomy (Chamberlain procedure);
* Endoscopic ultrasound guided node aspiration (EUS);
* Video-assisted thoracoscopy; OR
* Fine needle aspiration by image guidance.
* Endobronchial ultrasound (EBUS) or mediastinoscopy or other tissue sampling (at least 2 stations must be biopsied, with at least one station positive for N2 disease). If there are any mediastinal nodes suspicious by CT (\>1.5 cm) or PET in N3 stations, they must be biopsied. If biopsy proven involvement in an N3 station, the patient is excluded.
10. Mediastinal nodal biopsy or aspiration can only be omitted in the special circumstance in which ALL of the following are true:
* The tumor is left sided;
* The only mediastinal nodal involvement is a node visible in the AP (level 5) region on CT scan;
* Distinct primary tumor separate from the nodes; AND
* Biopsy proven non-small cell histology from the primary tumor.
11. No prior history of thoracic radiation.
12. Organ and marrow function definitions (example below)
* leukocytes ≥3,000/mcL
* absolute neutrophil count ≥1,500/mcL
* platelets ≥100,000/mcL
* Hemoglobin \>9.0 g/dL
* total bilirubin within normal institutional limits
* AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
* creatinine within normal institutional limits OR
* creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
13. Patients are capable of giving informed consent and/or have an acceptable surrogate capable of giving consent on the subject's behalf.
14. Nonpregnant and non-nursing. The effect of durvalumab on the fetus is unknown.
15. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 3 months after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free of menses \>1 year.
16. Evidence of postmenopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
* Women \<50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
* Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
17. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
18. Male patients must agree to use an adequate method of contraception starting with the first dose of study therapy through 12 weeks after the last dose of study therapy.
Exclusion Criteria:
1. Any prior treatment for NSCLC.
2. Prior thoracic radiation.
3. Patients with ≥Grade 2 peripheral neuropathy.
4. Any active or history of autoimmune disease (including any history of inflammatory bowel disease) or history of a syndrome that required systemic steroids or immunosuppressive medications, except for patients with vitiligo or resolved childhood asthma/atopy.
5. Patients requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \<10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
6. Patients with previous malignancies (except nonmelanoma skin cancers, in situ bladder, gastric, breast, colon or cervical cancers/dysplasia) 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.
7. History of solid organ transplant.
8. N3 nodal disease.
9. Mixed small cell/NSCLC will be excluded.
10. Pregnant or breastfeeding.
11. History of allogenic organ transplantation.
12. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], active 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 (eg, 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.
13. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
14. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated.
