Shifting patterns of care for the target population.

This is a prospective multi-center randomized clinical trial designed to demonstrate that daily online adaptive radiotherapy with concomitant chemotherapy for stage III non-small cell lung cancer (NSCLC) will result in decreased acute respiratory and esophageal toxicity compared with non-adaptive radiotherapy with concomitant chemotherapy. The timepoint for this assessment will be 3 months following the end of radiotherapy and will use the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Inclusion Criteria:

1. Provision of signed and dated informed consent form.

2. Histologically confirmed NSCLC

3. Clinical stage IIIA-IIIB (AJCC v8) disease who are either:

   1. Patients classified as non-operable by the treatment team
   2. Patients who refuse surgery

4. Clinical stage IIIC due to contralateral mediastinal lymph node involvement only (e.g., no contralateral hilar or any supraclavicular/cervical lymph node metastases). Mediastinal stations 2R and 4R are considered contralateral for patients whose primary tumor is within the left lung. Mediastinal stations 2L, 4L, 5, and 6 are considered contralateral for patients whose primary tumor is in the right lung.

5. Completed evaluation for metastatic disease with no distant metastases identified. Evaluation must include the following:

   1. History and physical examination within 30 days prior to enrollment.
   2. Whole body FDG PET-CT for staging within 60 days prior to enrollment
   3. Brain MRI or contrast enhanced CT within 60 days prior to enrollment.

6. ECOG performance status 0-2 and deemed clinically fit for chemoradiotherapy.

7. Age ≥18 years (or at least the local age of consent)

8. Patients must have normal organ and marrow function.

9. Serum creatinine ≤1.5 mg/dL within 60 days prior to enrollment.

10. Measurable disease must be present.

11. Negative urine or serum pregnancy test within 14 days prior to enrollment for women of childbearing potential.

Exclusion Criteria:

1. Contralateral hilar or any supraclavicular/cervical lymph nodes.
2. Baseline grade ≥3 dyspnea, or cough, or dysphagia.
3. Prior invasive non-skin malignancy unless disease free for a minimum of 3 years.
4. History of prior RT to the thorax.
5. Severe imaging artifact that, in the view of the local investigator, would preclude accurate identification of the thoracic anatomy and tumor targets on the cone beam CT (e.g., artifact created implanted cardiac device in proximity to the targets).
6. Evidence of malignant pleural effusion, defined as either FDG PET avidity within effusion fluid or presence of malignant cells identified by cytology of thoracentesis fluid.
7. Severe active chronic obstructive pulmonary disease or respiratory illness other than NSCLC precluding study therapy.
8. Hospitalization for chronic obstructive pulmonary disease or respiratory illness other than NSCLC within 1 year prior to study enrollment.
9. Women of childbearing potential and sexually active women not willing or able to use contraception.