Cemiplimab and Fianlimab Before Surgery for the Treatment of Stage IB-IIIB Non-Small Cell Lung Cancer

Eligibility Criteria

• * Age ≥ 18 years
• * Disease characteristics:
• * Histologically or cytologically confirmed stage IB-IIIB (N2) non-small cell lung cancer (NSCLC) per American Joint Committee on Cancer (AJCC) Cancer Staging Manual Eighth Edition
• * T4 tumors will only be eligible if they are defined as T4 based only on their size (more than 7 cm). All other T4 tumors will be ineligible.
• * Pathologic status of lymph nodes must be known
• * PD-L1 expression ≥ 1% by tumor proportion score (TPS) using immunohistochemistry (IHC)
• * Group A: PD-L1 expression ≥ 1% \< 50%
• * Group B: PD-L1 expression ≥ 50%
• * Complete surgical resection of the primary NSCLC must be deemed achievable by thoracic surgeon at screening
• * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• * Adequate pulmonary function ascertained by treating surgeon obtained ≤ 30 days prior to registration. A pre- or post-bronchodilator forced expiratory volume in 1 second (FEV1) of 1.0 L and \> 40% postoperative predicted value and diffusing capacity of the lungs for carbon monoxide (DLCO) \> 40% predicted value are required prior to enrollment
• * Hemoglobin ≥ 8.0 g/dL (obtained ≤ 15 days prior to registration)
• * Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained ≤ 15 days prior to registration)
• * Platelet count ≥ 100,000/mm\^3 (obtained ≤ 15 days prior to registration)
• * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 15 days prior to registration)
• * Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (obtained ≤ 15 days prior to registration)
• * Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained ≤ 15 days prior to registration)
• * Calculated creatinine clearance ≥ 45 ml/min using the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation (obtained ≤ 15 days prior to registration)
• * Negative pregnancy test done ≤ 8 days prior to registration, for persons of childbearing potential only
• * Provide written informed consent
• * Willingness to provide mandatory blood specimens for correlative research
• * Willingness to provide mandatory tissue specimens for correlative research
• * Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
• * Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown:
• * Pregnant persons
• * Nursing persons
• * Persons of childbearing potential or able to father a child who are unwilling to employ highly effective contraception during the study and up to 6 months after the last dose
• * Presence of targetable alterations \[Epiderman Growth Factor Receptor (EGFR), anaplastic lymphoma kinase (ALK), receptor tyrosine kinase (ROS1)\] in tumor
• * Unresectable or metastatic disease
• * Active or history of the following:
• * Prior systemic anti-cancer therapy or radiation therapy for the same cancer being studied in this protocol
• * Interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizing pneumonia), or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management, or pneumonitis within the last 5 years
• * Autoimmune disease (including any history of inflammatory bowel disease)
• * Any syndrome that required systemic steroids or immunosuppressive medications EXCEPTIONS: patients with vitiligo; resolved childhood asthma/atopy; residual hypothyroidism that requires only hormone replacement; or psoriasis not requiring systemic treatment, type-1 diabetes mellitus, or rheumatoid arthritis managed without disease modifying anti-rheumatic drugs or \>10 mg prednisone equivalent
• * Patients requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications ≤14 days prior to registration.
• * Patients with organ transplantation
• * History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias; or prior immune-related myocarditis
• * Uncontrolled intercurrent non-cardiac illness including, but not limited to:
• * Ongoing or active infection
• * Psychiatric illness/social situations Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
• * Any other conditions that would limit compliance with study requirements
• * Uncontrolled infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) or diagnosis of immunodeficiency that is related to, or results in chronic infection.
• * Patients with known HIV who have controlled infection \[undetectable viral load and cluster of differentiation 4 (CD4) count above 350 either spontaneously or on a stable antiviral regimen\] are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards.
• * Patients with known hepatitis B (hepatitis B surface antigen positive \[HBsAg+\]) who have controlled infection (serum hepatitis B virus 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 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.
• * Patients with HIV or hepatitis must be reviewed by a qualified specialist (e.g., infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
• * Receiving any other investigational agent which would be considered as a treatment for the primary malignancy
• * Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• * Prior malignancy active ≤ 3 years prior to registration except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast, or papillary thyroid
• * Known hypersensitivity to the active substances or to any of the excipients
• * Receipt of live vaccine ≤ 30 days prior to registration