Building upon the clinical experience of the investigators with the magnetic resonance (MR)-guided radiation therapy system and applying principals of hypofractionation toward the current treatment paradigm of concurrent chemoradiation and consolidation immunotherapy for locally advanced non-small cell lung cancer (NSCLC), this prospective, single-arm Phase II clinical trial with safety lead-in will test the feasibility and outcomes of this approach.

Inclusion Criteria:

• Histologically or cytologically proven diagnosis of non-small cell lung cancer.

• Inoperable or patient has refused surgery

• Clinical AJCC stage IIB or IIIA (AJCC, 8th ed.) with plans to be treated with concurrent chemoradiotherapy.

  • Recurrent non-small cell lung cancer is allowed, provided the intent of the current treatment is curative and there has been no prior radiation to the thorax (except prior SBRT per the protocol)
  • Prior chemotherapy, immunotherapy, or targeted therapy is permitted as long as patients have recovered from prior toxicities to grade ≤ 1
  • Clinical AJCC stage IIIB with plans to be treated with concurrent chemoradiotherapy are eligible if any of the following apply: (1) T3N2M0, (2) T4N2M0 (with T4 by size criteria (> 7 cm); T4 due to invasion or nodules in other ipsilateral lobe are excluded), (3) T1-2N3M0 where N3 disease is confined to no more than 2 contiguous nodal stations in the contralateral mediastinum. N3 disease with either contralateral hilar adenopathy, multistation contralateral mediastinal adenopathy that is either non-contiguous or >2 contiguous nodal stations, or any scalene or supraclavicular adenopathy are not eligible.
  • Clinical AJCC stage IIIC (T3-4N3M0) are eligible if N3 disease is confined to no more than 2 contiguous nodal stations in the contralateral mediastinum as above and, if applicable, T4 is due only to size >7 cm as above.

• Appropriate stage for protocol entry based upon the following minimum diagnostic workup:

  • History/physical examination within 30 days prior to registration
  • FDG-PET/CT scan and CT chest with or without contrast for staging within 60 days prior to registration
  • MRI scan with contrast of the brain (preferred) or CT scan of the brain with contrast within 60 days prior to registration

• Zubrod Performance Status 0-2 within 30 days prior to registration.

• Age ≥ 18 years.

• CBC/differential obtained within 30 days prior to registration, with adequate bone marrow function defined as follows:

  • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
  • Platelets ≥ 100,000 cells/mm3
  • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.)

• AST and ALT ≤ 1.5 upper limit of normal within 30 days prior to registration.

• Total bilirubin ≤ 1.5 upper limit of normal within 30 days prior to registration.

• Serum creatinine < 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL/min within 30 days prior to registration estimated by the Cockcroft-Gault formula:

Creatinine Clearance (male) = [(140 - age) x (wt in kg)] [(Serum Creatinine mg/dl) x (72)] Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male)

• Peripheral neuropathy ≤ grade 1 at the time of registration.
• Presence of measurable or evaluable disease by RECIST 1.1.
• Negative serum or urine pregnancy test within 2 weeks prior to registration for women of childbearing potential.
• Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study.
• Able to understand and willing to sign an IRB-approved informed consent document. Patients without capacity to make an informed consent decision must have a legally authorized representative sign the IRB-approved informed consent document on their behalf.

Exclusion Criteria:

• Severe, active comorbidity, defined as follows:

  • Unstable angina, history of myocardial infarction and/or congestive heart failure requiring hospitalization within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
  • Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients

• Prior radiotherapy to the thorax. An exception can be made for prior stereotactic body radiation therapy (SBRT) if there is no overlap with the protocol PTV and OAR constraints can still be achieved with a composite plan.

• Evidence of a concurrent primary malignancy, or any history of metastatic cancer.

• Currently receiving any other investigational agents.

• Pregnant or breastfeeding.

• Medical contraindication to receiving MRI imaging (including presence of a cardiac pacemaker).

• Autoimmune disease requiring active treatment, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. Specific instances of autoimmune disease are eligible and allowed on study, as below:

  • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone
  • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen.
  • Patients with eczema or psoriasis with dermatologic manifestations only, provided that the disease is well controlled at baseline and only requiring topical steroids, with no acute exacerbations within the last 12 months (requiring psoralen, ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.

• Chronic oral steroid use (greater than prednisone 10 mg orally once daily, or its equivalent) for any indication.