Neoadjuvant Chemo-Immunotherapy and Surgical Resection in Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node or Other High Risk Features

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

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

2. Any other tumor characteristic making it not suitable for resection as determined by treating surgeon.

2. Tumor with direct invasion of: myocardium, trachea, esophagus, vertebral body, or carina.

3. Any M1 disease.

4. \>2 involved N3 lymph node stations.

5. Biopsy-confirmed involvement of contralateral hilar and/or contralateral supraclavicular lymph nodes

6. Any other tumor- or patient-related characteristic that is prohibitive of attempted surgical resection upon multi-disciplinary team review.

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

8. 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 as assessed and confirmed by the study PI.

a. Patients with a history of stage I NSCLC treated with resection or radiotherapy are eligible for inclusion.

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

1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone.

2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen.

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

4. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible for the study provided all of following conditions are met:

i. Disease is well controlled at baseline and requires only low-potency topical corticosteroids ii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency oral corticosteroids within the previous 12 months

10. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.

11. Known active tuberculosis.

12. Known history of poorly controlled HIV.

a. Patients living with HIV are allowed to enroll if: (1) they are clinically stable on appropriate highly active anti-retroviral therapy (HAART) with undetectable HIV viral load and CD4 count \>350 and (2) the HAART regimen poses no unacceptable interactions with the prescribed anti-cancer therapies.

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

1. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.

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

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

15. Prior allogeneic stem cell or solid organ transplantation.

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

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

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

1. Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after PI confirmation has been obtained.

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

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

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

21. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 6 months after the final dose of study treatment.

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

What this study is about