Neoadjuvant Chemo-Immunotherapy and Surgical Resection in Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Involvement

Inclusion Criteria:

1. Age ≥ 18 years at time of signing the informed consent form (ICF).

2. Histologically or cytologically confirmed stage 3 B/C Non-Small Cell Lung Cancer (NSCLC) as assessed per the 8th American Joint Committee on Cancer (AJCC) withpathologically-confirmed contralateral mediastinal or ipsilateral supraclavicular (N3) lymph node involvement.

3. Primary tumor appropriate for resection with curative intent as assessed by thetreating surgeon prior to study enrollment.

4. Absence of major associated pathologies and co-morbidities that elevate surgery riskto a prohibitive level, as assessed by treating surgeon prior to study enrollment.

5. Pulmonary function capacity capable of tolerating the lung resection proposed by thetreating surgeon.

6. EGFR, ALK, wild-type assessed via any CLIA-certified tissue testing platform.Documentation of EGFR and ALK status is not required for pure squamous NSCLChistology.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

8. Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 21 days prior to initiation of study treatment:

9. Absolute Neutrophil count (ANC) ≥ 1.0 x 10^9/L (1000/uL) without granulocytecolony-stimulating factor support

10. Platelet count ≥ 100 x 10^9/L (100,000/uL) without transfusion

11. Hemoglobin ≥ 90 g/L (9.0 g/dL) (Patients may be transfused to meet thiscriterion.)

12. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) </= 3 xupper limit of normal (ULN)

13. Serum bilirubin </= 2.0 x ULN with the following exception: Patients with knownGilbert disease: serum bilirubin </= 3 x ULN

14. Creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gaultformula). If creatinine clearance determined by Cockcroft-Gault is <45 mL/min,another appropriate validated formula or 24hr urine collection may be used inconsultation with the study PI.

15. For patients not receiving therapeutic anticoagulation: INR (internationalnormalised ratio) and aPTT (activated partial thromboplastin time) </= 1.5 xULN. For patients receiving therapeutic anticoagulation: stable anticoagulantregimen defined as clinical stability on unchanged dose of therapeuticanticoagulation for ≥14 days.

16. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods, and agreement to refrainfrom donating eggs, as defined below: Women must remain abstinent or use highly effective contraceptive methods with afailure rate of < 1% per year during the treatment period and for at least 4 monthsafter the final dose of study treatment. Women must refrain from donating eggsduring this same period. A woman is considered to be of childbearing potential if she is postmenarchal, hasnot reached a postmenopausal state (≥ 12 continuous months of amenorrhea with noidentified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may beadapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives that inhibitovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the patient. Periodicabstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) andwithdrawal are not adequate methods of contraception.

17. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, and agreement to refrain from donating sperm, as definedbelow:

With a female partner of childbearing potential who is not pregnant, or a female partner who is pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the final dose of study treatment. Men must refrain from donating sperm during this this same period.

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.

Exclusion Criteria:

1. NSCLC with histology containing any of the following: large cell neuroendocrinecarcinoma, small cell lung cancer.

2. Primary tumor not deemed appropriate for surgical resection as assessed by treatingsurgeon.

3. Tumor with direct invasion of: mediastinum, diaphragm, heart, great vessels,trachea, esophagus, vertebral body, or carina.

4. Any other tumor characteristic making it not suitable for resection asdetermined by treating surgeon.

5. Any prior systemic therapy for index lung cancer, including immunotherapy,chemotherapy.

6. History of malignancy requiring systemic therapy within 2 years prior to screening,with the exception of malignancies with a negligible risk of metastasis or death asassessed and confirmed by the study PI. (Patients with a history of stage I NSCLCtreated with resection or radiotherapy are eligible for inclusion.)

7. Active or history of clinically significant autoimmune disease that, in the opinionof the investigator, could compromise the health and safety of the patient iftreated with anti-PD1 immunotherapy. Notable exceptions include:

8. Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone.

9. Patients with controlled Type 1 diabetes mellitus who are on an insulinregimen.

10. Active or history of adrenal insufficiency on stable steroid regimen.

11. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only are eligible for the study provided all offollowing conditions are met: Disease is well controlled at baseline andrequires only low-potency topical corticosteroids; No occurrence of acuteexacerbations of the underlying condition requiring psoralen plus ultraviolet Aradiation, methotrexate, retinoids, biologic agents, oral calcineurininhibitors, or high-potency oral corticosteroids within the previous 12 months

12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan.

13. Known active tuberculosis.

14. Known history of poorly controlled HIV. Patients living with HIV are allowed toenroll if: (1) they are clinically stable on appropriate highly activeanti-retroviral therapy (HAART) with undetectable HIV viral load and CD4 count >350and (2) the HAART regimen poses no unacceptable interactions with the prescribedanti-cancer therapies.

15. Known history of poorly controlled hepatitis B or hepatitis C

16. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serumhepatitis B virus (HBV) DNA PCR that is below the limit of detection ANDreceiving anti-viral therapy for hepatitis B) are permitted. Patients withcontrolled infections must undergo periodic monitoring of HBV DNA per localstandards and must remain on anti-viral therapy for at least 6 months beyondthe last dose of investigational study drug.

17. Patients who are known hepatitis C virus (HCV) antibody positive (HCV Ab+) whohave controlled infection (undetectable HCV RNA by PCR either spontaneously orin response to a successful prior course of anti-HCV therapy) are permitted.

18. Severe infection within 3 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection (includingCOVID-19), bacteremia, or severe pneumonia that, in the opinion of the investigator,may impact patient safety.

19. Prior allogeneic stem cell or solid organ transplantation.

20. Any treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during study treatmentor within 5 months after the final dose of study treatment.

21. Significant vascular and cardiovascular disease (e.g., New York Heart AssociationClass II or greater heart failure, unstable arrhythmia, aortic aneurysm requiringsurgical repair or recent peripheral arterial thrombosis - including but not limitedto myocardial infarction, transient ischemic attack, stroke or unstable angina)within 6 months prior to study treatment initiation.

22. Treatment with systemic immunosuppressive medication (including, but not limited to:corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, oranticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

23. Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study after PIconfirmation has been obtained.

24. Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

25. Any prior use of an immune checkpoint blockade therapy including agents directedagainst CTLA-4, PD-1, and PD-L1.

26. History of severe allergic reaction or hypersensitivity to study drug components.

27. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatmentor within 6 months after the final dose of study treatment. Women of childbearingpotential must have a negative serum pregnancy test result within 14 days prior toinitiation of study treatment.