Summary

This phase III trial compares the effect of adding stereotactic body radiation therapy (SBRT) to the usual treatment (conventional image guided radiation therapy [IGRT] and chemotherapy followed by immunotherapy with durvalumab) versus the usual treatment alone in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be treated by surgery (inoperable). SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. IGRT is a type of radiation that uses a computer to create a picture of the tumor, to help guide the radiation beam during therapy, making it more accurate and causing less damage to healthy tissue. Usual chemotherapy used in this trial consists of combinations of the following drugs: cisplatin, carboplatin, paclitaxel, nab-paclitaxel, pemetrexed, and etoposide. Cisplatin and carboplatin are in a class of medications known as platinum-containing compounds. Cisplatin works by killing, stopping, or slowing the growth of tumor cells. Carboplatin works in a way similar to the anticancer drug cisplatin but may be better tolerated than cisplatin. Carboplatin works by killing, stopping, or slowing the growth of tumor cells as well. Paclitaxel is in a class of medications called antimicrotubule agents. It works by stopping the growth and spread of tumor cells. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by blocking the action of a certain substance in the body that may help tumor cells multiply. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill tumor cells. Immunotherapy with durvalumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Adding SBRT to the usual treatment of IGRT with chemotherapy and immunotherapy may be more effective at treating patients with locally-advanced non-small cell lung cancer than giving the usual treatment alone.

Objectives

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.

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. Patients also undergo CT and/or positron emission tomography (PET)/CT during follow-up.

ARM II: Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel 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. 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.

Eligibility

1. Pathologically (histologically or cytologically) proven diagnosis of stage II or III (American Joint Committee on Cancer [AJCC] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration * Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene) * Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible
2. The patient must be deemed clinically appropriate for curative intent definitive combined 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 of the brain (if available, contrast is preferred for all neuroimaging) prior to registration; * 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 used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT
3. No evidence of distant metastases based on FDG PET/CT scan obtained within 60 days of registration
4. Primary tumor =< 7 cm
5. Age >= 18
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
7. Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at the discretion of the treating physician, to allow for treatment with chemotherapy and concurrent radiation therapy
8. Creatinine clearance >= 25 mL/min by the Cockcroft-Gault (C-G) equation
9. Subjects with non-malignant pleural effusion are eligible provided the effusion is not known or demonstrated to be an exudative effusion * If a pleural effusion is present, the following criteria must be met to exclude malignant involvement: ** When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative; ** Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible
10. Medical history consistent with the patient being amenable, at the discretion of the treating physician, to allow for treating with consolidation immunotherapy. Patients with known EGFR/ALK mutation at the time of registration are eligible, and these patients can be treated with consolidation durvalumab or chemotherapy at the discretion of the treating physician
11. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen
12. Negative pregnancy test =< 14 days prior to registration for participants of childbearing potential
13. The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Treatment Sites in Georgia