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

Inclusion Criteria:

• Age ≥ 18 years

• Disease characteristics:

• Histologically or cytologically confirmed stage IB-IIIB (N2) non-small celllung cancer (NSCLC) per American Joint Committee on Cancer (AJCC) CancerStaging Manual Eighth Edition

• T4 tumors will only be eligible if they are defined as T4 based only on theirsize (more than 7 cm). All other T4 tumors will be ineligible.

• Pathologic status of lymph nodes must be known for suspicious or enlarged lymphnodes. Note: suspicious or enlarged lymph nodes must be discussed withsponsor/principal investigator.

• PD-L1 expression ≥ 1% by tumor proportion score (TPS) usingimmunohistochemistry (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 bythoracic surgeon at screening

• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1NOTE: Tumor lesions in a previously irradiated area are not considered measurabledisease; 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 priorto registration. A pre- or post-bronchodilator forced expiratory volume in 1 second (FEV1) of 1.0 L or > 40% postoperative predicted value or diffusing capacity of thelungs for carbon monoxide (DLCO) > 40% predicted value are required prior toenrollment

• Hemoglobin ≥ 8.0 g/dL (obtained ≤ 15 days prior to registration)

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior toregistration)

• 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 toregistration)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (obtained ≤ 15 days prior to registration)

• Prothrombin time (PT)/international normalized ratio (INR)/activated partialthromboplastin time (aPTT) ≤ 1.5 x ULN OR if patient is receiving anticoagulanttherapy and INR or aPTT is within target range of therapy (obtained ≤ 15 days priorto registration)

• Calculated creatinine clearance ≥ 45 ml/min using the Cockroft-Gault formula (obtained ≤ 15 days prior to registration)

• Negative pregnancy test done ≤ 8 days prior to registration, for persons ofchildbearing 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 ActiveMonitoring Phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, thegenotoxic, mutagenic, and teratogenic effects of which on the developing fetus andnewborn are unknown:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential or able to father a child who are unwillingto employ highly effective contraception during the study and up to 6 monthsafter 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 cancerbeing studied in this protocol

• Interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizingpneumonia), or active, noninfectious pneumonitis that requiredimmune-suppressive doses of glucocorticoids to assist with management, orpneumonitis within the last 5 years

• Autoimmune disease (including any history of inflammatory bowel disease)

• Any syndrome that required systemic steroids or immunosuppressive medicationsEXCEPTIONS: patients with vitiligo; resolved childhood asthma/atopy; residualhypothyroidism that requires only hormone replacement; or psoriasis notrequiring systemic treatment, type-1 diabetes mellitus, or rheumatoid arthritismanaged without disease modifying anti-rheumatic drugs or >10 mg prednisoneequivalent

• Patients requiring systemic treatment with either corticosteroids (> 10 mg dailyprednisone equivalents) or other immunosuppressive medications ≤14 days prior toregistration.

NOTE: Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease

• Patients with organ transplantation

• History of myocardial infarction ≤ 6 months prior to registration, or congestiveheart failure requiring use of ongoing maintenance therapy for life-threateningventricular 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 diseasethat 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 chronicinfection.

Note: No testing is required for this study unless mandated by local health authority.

EXCEPTIONS:

• Patients with known HIV who have controlled infection [undetectable viral load andcluster of differentiation 4 (CD4) count above 350 either spontaneously or on astable 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+]) whohave controlled infection (serum hepatitis B virus DNA polymerase chain reaction (PCR) that is below the limit of detection AND receiving anti-viral therapy forhepatitis B) are permitted. Patients with controlled infections must undergoperiodic monitoring of HBV DNA per local standards and must remain on anti-viraltherapy 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 havecontrolled infection (undetectable HCV ribonucleic acid (RNA) by PCR eitherspontaneously or in response to a successful prior course of anti-HCV therapy) arepermitted.

• Patients with HIV or hepatitis must be reviewed by a qualified specialist (e.g.,infectious disease or hepatologist) managing this disease prior to commencing andregularly throughout the duration of their participation in the trial NOTE: Patientsknown to be HIV positive, but without clinical evidence of an immunocompromisedstate, are eligible for this trial

• Receiving any other investigational agent which would be considered as atreatment for the primary malignancy

• Co-morbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entryinto this study or interfere significantly with the proper assessment of safetyand toxicity of the prescribed regimens

• Patients with a prior or concurrent malignancy whose natural history ortreatment does have the potential to interfere with the safety or efficacyassessment of the investigational regimen

• Known hypersensitivity to the active substances or to any of the excipients

• Receipt of live vaccine ≤ 30 days prior to registration