Stereotactic Body Radiation Therapy With or Without Nivolumab in Treating Patients With Stage I-IIA or Recurrent Non-small Cell Lung Cancer

Inclusion Criteria:

• Histological confirmation of non-small cell lung cancer (NSCLC) by either biopsy orcytology is required for the primary diagnosis and is recommended for recurrentdisease. The following primary cancer types are eligible: squamous cell carcinoma,adenocarcinoma (with or without bronchioloalveolar carcinoma features), large cellcarcinoma (with or without neuroendocrine features), neuroendocrine carcinoma (either NSCLC with neuroendocrine features or atypical carcinoids, but not smallcell lung carcinoma), bronchioloalveolar cell carcinoma, or non-small cell carcinomanot otherwise specified

• Stage I or selected stage IIa according to the 7th version of the InternationalAssociation for the Study of Lung Cancer (IASLC) system: stage I (T1 or T2a [tumorsize =< 5 cm] N0M0) stage IIa (T2 [tumor size > 5 cm but =< 7 cm] N0M0)

• Patients with multiple primary lung tumors (defined below) are eligible:

• Synchronous tumors (diagnosed within 6 months [mo]),

• Different histology,

• Same histology,

• Second tumor in different lobed or lung;

• Metachronous tumors (diagnosed > 6 mo apart),

• Different histology,

• Same histology,

• Second tumor in different lobe or lung,

• Tumor-free interval of at least 4 years (y)

• Patient with multiple primary lung tumors who will receive multiple courses ofstereotactic body radiation therapy (SBRT) (50Gy in 4Fx or 70Gy in 10Fx) areeligible

• Patients with isolated lung parenchymal recurrent/persistent NSCLC (histology asdefined in eligibility criterion 1) after prior definitive surgery orradiotherapy/chemotherapy, when the lesion or lesions are suitable for SABR, arealso eligible.

• Patients with a single metastatic focus in the lung parenchyma with no otherlesions are also eligible, because this presentation is challenging todistinguish from recurrent disease.

• Recurrent disease can be in the same lobe or a different lobe but should notinvade critical structures (esophagus, brachial plexus, major vessels, heart,spinal cord); should not involve any lymph node; and should not include anyother suspicious lesions in the lung or any other locations.

• Any prior therapy (surgery, radiotherapy, or systemic) must have been completedat least 12 weeks before administration of the study drug.

• Tumors should be =< 7 cm (measured by CT imaging in the lung window setting)with N0M0; PET) imaging is required for restaging (per eligibility criterion)and any lymph node suspected of harboring tumor should be confirmed by biopsy (per eligibility criterion)

• Both Chest CT and PET/CT are required within 16 weeks and at least one of them needsto be done within 12 weeks (plus/minus 1 week). Any lymph node suspected ofharboring disease based on its shape, size, or PET standardized uptake value (SUV)should be discussed by treating physician and diagnostic radiologist

• Patients with medically inoperable stage I disease (T1 or T2a [tumor size =< 5 cm]N0M0) or selected stage IIa disease (T2 [tumor size > 5 cm but =< 7 cm] N0M0) whohave poor lung function or other significant cardiovascular or other comorbiditysuch as diabetes are eligible. Patients with operable disease who choose to haveSABR are also eligible.

• The standard justification for medical inoperability is based on pulmonaryfunction and can include any of the following: baseline forced expiratoryvolume in 1 second (FEV1) < 50% of predicted value; diffusion capacity < 50% ofpredicted value; baseline hypoxemia or hypercapnia; exercise oxygen consumption < 50% of predicted value; severe pulmonary hypertension; severe cerebral,cardiac, or peripheral vascular disease; and severe chronic heart disease

• Patients must have a Zubrod performance status score of 0-2 (2 is included herebecause such patients are typically > 70 years old and cannot tolerate surgery)

• The following mandatory staging studies must be done within 12 weeks before studyregistration:

• Chest CT or PET/CT scans of both lungs, the mediastinum, adrenal glands andrest of the body; primary tumor dimension will be measured on diagnostic CT andagain on simulation CT using the lung window setting.

• Mediastinoscopy or endobronchial ultrasound-guided biopsy of the mediastinallymph nodes is recommended and required for any patients with PET/CT or CTfindings suggesting lymph node involvement.

• Brain magnetic resonance imaging (MRI) or CT scan if symptoms or signs suggestbrain metastases.

• Invasive mediastinal staging: For all patients with CT or PET evidence of hilarinvolvement (level 10) or with mediastinal lymph nodes > 1.0 cm in the shortestdiameter or clinically suspicious by treating physician and/or radiologist,disease must be staged by cervical mediastinoscopy, esophageal endoscopicultrasound-guided biopsy, or endobronchial ultrasound-guided biopsy

• For patients with left-sided tumors and enlarged nodes (> 1.0 cm in the shortestdiameter) on the aortopulmonary window setting, the aortopulmonary nodes must bebiopsied by extended mediastinoscopy, Chamberlain procedure, video-assistedthoracoscopic surgery (VATS) approach, or ultrasound-guided biopsy to ensure thatthe patient does not have N2 disease. At the time of cervical mediastinoscopy,esophageal endoscopic ultrasound-guided biopsy, or endobronchial ultrasound-guidedbiopsy, the following nodal stations must be examined and biopsied, if present:

• Ipsilateral nodal station 4

• Contralateral nodal station level 4, and

• Subcarinal nodes (level 7) For left-sided tumors, any lymph node in thesuperior or anterior mediastinum > 1.0 cm in the shortest axis on CT orpositive on PET must be identified and biopsied. Eligibility requires that anyPET-positive mediastinal or distant sites must be biopsy-negative. However, ifthe treating physician and diagnostic radiologist strongly suspect PETpositivity, the patient should not be enrolled even if the biopsy is negative (to exclude patients with false-negative biopsy)

• All patients must sign a study-specific consent form

• All patients (men & women) of childbearing potential should use a method of birthcontrol that is effective for them throughout their participation in this study.

• Women of childbearing potential should use an adequate contraceptive method toavoid pregnancy for 5 months (30 days plus the time required for nivolumab toundergo five half-lives) after the last dose of investigational drug; must havea negative serum or urine pregnancy test (minimum sensitivity 25 IU/L orequivalent units of human chorionic gonadotropin [HCG]) within 24 hours beforethe start of nivolumab; and must not be breastfeeding.

• Men who are sexually active with women of childbearing potential must use acontraceptive method with a failure rate of less than 1% per year; menreceiving nivolumab will be instructed to use contraception for 7 months afterthe last dose of nivolumab.

• Women who are not of childbearing potential (i.e. are postmenopausal orsurgically sterile) & azoospermic men do not require contraception

• White blood cell (WBC) >= 2000/uL (within 30 days before study registration)

• Neutrophils (Neuts) >= 1500/uL (within 30 days before study registration)

• Platelets (PLT) >= 100 x 10^3/uL (within 30 days before study registration)

• Hemoglobin (HGB) > 9.0 g/dL (within 30 days before study registration)

• Serum creatinine =< 2 x upper limit of normal (ULN) or creatinine clearance (calculated with the Cockcroft-Gault formula) >= 30 mL/min (within 30 days beforestudy registration)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (within 30 days before study registration)

• Total bilirubin (Bili T) =< 1.5 x ULN (although patients with Gilbert syndrome canhave total bilirubin < 3.0 mg/dL (within 30 days before study registration)

Exclusion Criteria:

• Patients with tumors > 7 cm or tumors involving the main bronchus or associatedvessels or tumors that invade any critical structures (such as esophagus, brachialplexus, heart, mediastinal major vessels) are not suitable for SABR

• Patients with direct evidence of regional or distant metastases after appropriatestaging studies, or with synchronous non-lung primary or prior non-lung malignancy (other than nonmelanomatous skin cancer or in situ cancer) diagnosed within the past 3 years are not eligible. Patients with a history of curable non-lung cancer up to 3years before registration and have been cancer-free for 2 years are eligible

• Patients who have received previous immunotherapy with PD1 or CTLA4 antibodies arenot eligible

• Patients with plans to receive other concomitant local therapy (including standardfractionated radiotherapy and surgery) or other systemic therapy (includingchemotherapy, target therapy and other type of immunotherapy or investigativeagents) while on this protocol, except at disease progression, are not eligible

• Female patients who are pregnant or lactating are not eligible (because treatmentinvolves unforeseeable risks to the embryo or fetus)

• Patients for whom SABR plans cannot meet the minimum requirement of target coverageand dose-volume constraints of critical structures (see SABR treatment planningsection) are not eligible

• Patients who have active, known, or suspected autoimmune disease are not eligible.However, patients with vitiligo, type I diabetes mellitus, residual hypothyroidismdue to an autoimmune condition that requires only hormone replacement, psoriasis notrequiring systemic treatment, or conditions not expected to recur in the absence ofan external trigger are permitted to enroll

• Patients with a known history of antibodies to human immunodeficiency virus (HIV) -1or -2 are not eligible. Patients with live vaccines

• Patients with a known positive test for hepatitis B virus surface antigen (HBV sAg)or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronicinfection are not eligible

• Patients who have a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14days of study drug administration are not eligible. However, inhaled or topicalsteroids, adrenal replacement doses, and > 10 mg daily prednisone equivalents arepermitted in the absence of active autoimmune disease

• Patients with allergies or adverse drug reactions to the following are not eligible:

• History of allergy to study drug components;

• History of severe hypersensitivity reaction to any monoclonal antibody

• Patients who have had prior treatment with an anti-PD1, anti-PDL1, anti-PDL2,anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cellcostimulation or immune checkpoint pathways are not eligible

• Patients are known to have contraindications to radiotherapy