Neoadjuvant Cemiplimab with Histology-Specific Chemotherapy Followed by Surgery and Adjuvant Cemiplimab for the Treatment of Locally Advanced Non-Small Cell Lung Cancer, NEO-SURG Trial

Inclusion Criteria

• Age ≥ 18 years at time of signing informed consent form (ICF)
• Histologically or cytologically confirmed stage III B/C NSCLC as assessed per the 8th American Joint Committee on Cancer (AJCC) with pathologically-confirmed contralateral mediastinal or ipsilateral supraclavicular (N3) lymph node involvement
• Primary tumor and involved lymph nodes appropriate for resection/removal with curative intent as assessed by the treating surgeon prior to study enrollment
• 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
• Pulmonary function capacity capable of tolerating the lung resection proposed by the treating surgeon
• EGFR, ALK, wild-type assessed via any Clinical Laboratory Improvement Act (CLIA)-certified tissue testing platform. * Documentation of EGFR and ALK status is not required for pure squamous NSCLC histology
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L (1000/µL) without granulocyte colony-stimulating factor support (obtained within 21 days prior to initiation of study treatment)
• Platelet count ≥ 100 × 10^9/L (100,000/µL) without transfusion (obtained within 21 days prior to initiation of study treatment)
• Hemoglobin ≥ 90 g/L (9.0 g/dL) (obtained within 21 days prior to initiation of study treatment) * Patients may be transfused to meet this criterion
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN) (obtained within 21 days prior to initiation of study treatment)
• Serum bilirubin ≤ 2.0 × ULN with the following exception: * Patients with known Gilbert disease: serum bilirubin ≤ 3 × ULN (obtained within 21 days prior to initiation of study treatment)
• Creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gault formula) (obtained within 21 days prior to initiation of study treatment) * 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 principal investigator (PI)
• For patients not receiving therapeutic anticoagulation: international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (obtained within 21 days prior to initiation of study treatment) * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen defined as clinical stability on unchanged dose of therapeutic anticoagulation for ≥ 14 days
• 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: Women must remain abstinent or use highly effective contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 4 months after the final dose of study treatment. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 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.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: 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

• NSCLC with histology containing any of the following: large cell neuroendocrine carcinoma, small cell lung cancer
• Primary tumor not deemed appropriate for surgical resection as assessed by treating surgeon. * Tumor with direct invasion of: mediastinum, diaphragm, heart, great vessels, trachea, esophagus, vertebral body, or carina. * Any other tumor characteristic making it not suitable for resection as determined by treating surgeon. * Contralateral lung (M1a) disease * > 2 involved N3 lymph node stations
• Biopsy-confirmed involvement of contralateral hilar and/or contralateral supraclavicular lymph nodes
• Any prior systemic therapy for index lung cancer, including immunotherapy, chemotherapy
• 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
• 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 antiPD1 immunotherapy. Notable exceptions include: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone. * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen. * Active or history of adrenal insufficiency on stable steroid regimen. * 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
• 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
• Known active tuberculosis
• Known history of poorly controlled HIV. * Patients living with HIV are allowed to enroll if: ** They are clinically stable on appropriate highly active anti-retroviral therapy (HAART) with undetectable HIV viral load and CD4 count > 350 and ** The highly active antiretroviral therapy (HAART) regimen poses no unacceptable interactions with the prescribed anti-cancer therapies.
• Known history of poorly controlled hepatitis B or hepatitis C * Patients with known hepatitis B (hepatitis B surface antigen positive [HepBsAg+]) who have controlled infection (serum hepatitis B virus deoxyribonucleic acid [DNA] polymerase chain reaction (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 hepatitis B virus (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. * Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV ribonucleic acid [RNA] by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted
• 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
• 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
• 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
• Treatment with systemic immunosuppressive medication (including, but not limited to: corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF]-alpha [α] 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: * 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. * 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
• Any prior use of an immune checkpoint blockade therapy including agents directed against CTLA-4, PD-1, and PD-L1
• History of severe allergic reaction or hypersensitivity to study drug components
• 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