Testing the Addition of High Dose, Targeted Radiation to the Usual Treatment for Locally-Advanced Inoperable Non-Small Cell Lung Cancer

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of non-operablestage IIB or III, node positive (American Joint Committee on Cancer [AJCC] eighthedition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior toregistration

• Patients must have an identified primary tumor and at least one nodalmetastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal,supraclavicular/scalene)

• Up to 4 cycles of systemic therapy received prior to registration for thecurrent study cancer is allowable; any prior chemotherapy for a differentcancer is also permissible

• Patients who refuse surgery, in addition to those who are technicallyunresectable or medically inoperable, are eligible.

• Patients with separate tumor nodules in the same lobe of the primary tumor areeligible

• The patient must be deemed clinically appropriate for curative intent definitivecombined modality therapy, based on the following staging assessments:

• History/physical examination prior to registration;

• Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan ofthe brain (if available, contrast is preferred for all neuroimaging) prior toregistration;

• CT chest with IV contrast (if contrast is available and unless contraindicated,such as for abnormal kidney function) prior to registration. PET/CT may be usedif the CT portion is of identical diagnostic quality as achieved in astand-alone CT

• No evidence of distant metastases based on FDG PET/CT scan obtained within 60 daysof registration

• Primary tumor =< 7 cm

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at thediscretion of the treating physician, to allow for treatment with chemotherapy andconcurrent radiation therapy

• Creatinine clearance >= 25 mL/min by the Cockcroft-Gault (C-G) equation

• Subjects with non-malignant pleural effusion are eligible provided the effusion isnot known or demonstrated to be an exudative effusion

• If a pleural effusion is present, the following criteria must be met to excludemalignant involvement:

• When pleural fluid is visible on both the CT scan and on a chest x-ray, apleuracentesis is required to confirm that the pleural fluid iscytologically negative;

• Effusions that are minimal (i.e., not visible on chest x-ray) that are toosmall to safely tap are eligible

• Medical history consistent with the patient being amenable, at the discretion of thetreating physician, to allow for treating with consolidation immunotherapy. Patientswith known EGFR/ALK/other driver mutation at the time of registration are eligible,and these patients can be treated with consolidation systemic therapy at thediscretion of the treating physician

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen

• Negative pregnancy test =< 14 days prior to registration for participants ofchildbearing potential

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Prior radiotherapy to the study cancer (local recurrence). Prior radiotherapy for adifferent cancer/condition to the region of the study cancer that would result inoverlap of radiation therapy fields that is determined by the treating physician toimpede the treatment of the study malignancy

• Patients without identifiable primary tumor and at least 1 pathologically enlargedlymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1radiographically-involved lymph node is required, but pathologic confirmation ofinvolvement is not mandated

• Centrally located primary tumor < 2 cm from involved nodal disease that would resultin significant overlap of the primary SBRT and nodal radiation fields. This does notinclude proximity to involved segmental and subsegmental lymph nodes (levels 13 and

14. that would not result in overlap of dose to the proximal bronchial tree oresophagus. Centrally located is defined as within or touching the zone of theproximal bronchial tree, which is a volume 2 cm in all directions around theproximal bronchial tree (carina, right and left main bronchi, right and left upperlobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchusright and left lower lobe bronchi)

• Participants who are pregnant or unwilling to discontinue nursing

• Participants of childbearing potential (participants who may become pregnant or whomay impregnate a partner) unwilling to use highly effective contraceptives duringtherapy and for the Food and Drug Administration (FDA)-labeled contraceptiontimeframe required after the final dose of the selected systemic therapy regimen,because the treatment in this study may be significantly teratogenic