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

PRIMARY OBJECTIVES: I. To compare the overall survival in patients with stage II-IIIC inoperable node-positive non-small cell lung cancer (NSCLC) after image guided, motion-managed conventional radiotherapy to the primary tumor and nodal metastases (Arm 1) or after image guided, motion-managed stereotactic body radiation therapy (SBRT) to the primary tumor followed by conventionally fractionated radiotherapy to nodal metastases (Arm 2) both given with concurrent platinum-based chemotherapy. II. To compare progression-free survival between the experimental arm (Arm 2) and control arm (Arm 1). SECONDARY OBJECTIVES: I. To compare objective response rate (as defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\] 1.1) between the experimental arm and control arm. II. To compare the rate of local control between the experimental arm and control arm. III. To compare patterns of failure (primary, locoregional, or distant) between the experimental arm and control arm. IV. To compare changes in pulmonary function (forced expiratory volume in 1 second \[FEV1\] and diffusion capacity of the lung for carbon monoxide \[DLCO\] assessed at randomization and at 6- and 12- months following completion of radiation therapy) between the experimental arm and control arm. V. To compare changes in quality of life and patient-reported outcomes assessed from pre-treatment to 3 months following radiation therapy of each treatment arm. VI. To determine acute and late toxicity profiles of each treatment arm as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v5. EXPLORATORY OBJECTIVES: I. To characterize and compare longitudinal quality of life and patient-reported outcomes of each treatment arm. II. To collect biospecimens at baseline, after SBRT (for Arm 2 patients), during last 2 weeks of chemoradiation, and after first dose of consolidation therapy, to allow for future analyses. III. To collect 4-dimensional (4D) computed tomography (CT) planning scans and radiation dose to calculate regional lung ventilation and explore pre-treatment 4D-CT based ventilation to predict pulmonary toxicity. IV. To characterize clinical outcomes, toxicities and changes in pulmonary function and quality of life among patients receiving proton and photon radiotherapy. V. To develop and characterize a machine learning/artificial intelligence algorithm for radiotherapy planning and/or quality assurance. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel intravenously (IV) followed by carboplatin IV weekly (Q7D) during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or positron emission tomography (PET)/CT during follow-up. ARM II: Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Patients are followed up every 3 months for 1 year, every 6 months during years 2 and 3, and then yearly after that for the duration of the study.