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

Eligibility 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) with pathologically-confirmed contralateral mediastinal or ipsilateral supraclavicular (N3) lymph node involvement.
• 3. Primary tumor appropriate for resection with curative intent as assessed by the treating surgeon prior to study enrollment.
• 4. Absence of major associated pathologies and co-morbidities that elevate surgery risk to a prohibitive level, as assessed by treating surgeon prior to study enrollment.
• 5. Pulmonary function capacity capable of tolerating the lung resection proposed by the treating 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 NSCLC histology.
• 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 8. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 21 days prior to initiation of study treatment:
• 1. Absolute Neutrophil count (ANC) ≥ 1.0 x 10\^9/L (1000/uL) without granulocyte colony-stimulating factor support
• 2. Platelet count ≥ 100 x 10\^9/L (100,000/uL) without transfusion
• 3. Hemoglobin ≥ 90 g/L (9.0 g/dL) (Patients may be transfused to meet this criterion.)
• 4. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \</= 3 x upper limit of normal (ULN)
• 5. Serum bilirubin \</= 2.0 x ULN with the following exception: Patients with known Gilbert disease: serum bilirubin \</= 3 x ULN
• 6. Creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gault formula). If creatinine clearance determined by Cockcroft-Gault is \<45 mL/min, another appropriate validated formula or 24hr urine collection may be used in consultation with the study PI.
• 7. For patients not receiving therapeutic anticoagulation: INR (international normalised ratio) and aPTT (activated partial thromboplastin time) \</= 1.5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen defined as clinical stability on unchanged dose of therapeutic anticoagulation for ≥14 days.
• 9. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
• 10. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
• 1. NSCLC with histology containing any of the following: large cell neuroendocrine carcinoma, small cell lung cancer.
• 2. Primary tumor not deemed appropriate for surgical resection as assessed by treating surgeon.
• 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.
• 3. Any prior systemic therapy for index lung cancer, including immunotherapy, chemotherapy.
• 4. 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. (Patients with a history of stage I NSCLC treated with resection or radiotherapy are eligible for inclusion.)
• 5. 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: Disease is well controlled at baseline and requires only low-potency topical corticosteroids; 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
• 6. 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.
• 7. Known active tuberculosis.
• 8. Known history of poorly controlled HIV. 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.
• 9. 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 (HBV) 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 (HCV) 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.
• 10. 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.
• 11. Prior allogeneic stem cell or solid organ transplantation.
• 12. 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.
• 13. 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.
• 14. 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.
• 15. Any prior use of an immune checkpoint blockade therapy including agents directed against CTLA-4, PD-1, and PD-L1.
• 16. History of severe allergic reaction or hypersensitivity to study drug components.
• 17. 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.