This phase III trial studies how well atezolizumab added to the usual radiation therapy works in treating patients with stage I-IIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy, such as stereotactic body radiation therapy, uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving atezolizumab and radiation therapy may work better than radiation therapy alone in treating patients with early non-small cell lung cancer.

PRIMARY OBJECTIVE:

I. To compare overall survival (OS) in patients with inoperable, early stage non-small cell lung cancer (NSCLC) randomized to stereotactic body radiation therapy (SBRT) with or without atezolizumab.

SECONDARY OBJECTIVES:

I. To compare investigator-assessed progression-free survival (IA-PFS) between the arms.

II. To compare progression free survival (PFS) by blinded independent centralized review (BIRC) between the arms in a random subset of patients.

III. To evaluate distant, locoregional, and local failure rates within each treatment arm.

IV. To evaluate the frequency and severity of toxicities within each treatment arm.

ADDITIONAL OBJECTIVE:

I. To collect specimens for banking.

HEALTH-RELATED QUALITY OF LIFE (HRQOL) OBJECTIVE:

I. This objective will not be met, as the study was closed following the first interim analysis.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Starting on day 1 cycle 3, patients also undergo SBRT for 3-8 treatments every 2 days or once daily (QD) over 1-3 weeks. Patients undergo fludeoxyglucose F-18 (FDG)-positron emission tomography/computed tomography (PET/CT) during screening. Patients undergo blood sample collection and CT scans throughout the trial.

ARM B: Beginning 21 days after randomization, patients undergo SBRT for 3-8 treatments every 2 days or QD over 1-3 weeks. Patients undergo FDG-PET/CT during screening. Patients undergo blood sample collection and CT scans throughout the trial.

After completion of study treatment, patients are followed for 5 years after randomization.

Inclusion Criteria:

• Patient must have histologically or cytologically proven stage I-IIA or limited T3N0M0 non-small cell lung cancer (NSCLC), without radiographic evidence of nodal or distant involvement (N0M0). Patient may have T3 disease with the exclusion of pericardial involvement. Patients with multifocal tumors with no more than two lesions confirmed or suspected to be synchronous early stage NSCLCs are eligible provided at least one lesion is histologically or cytologically proven to be NSCLC and meets one or more high-risk features

• Disease must have one or more of the following high-risk features:

  • Tumor diameter >= 2 cm (inclusive of any non-solid, ground glass component) as assessed by diagnostic CT
  • Tumor standard uptake value (SUV) max >= 6.2 as assessed by FDG PET/CT
  • Moderately differentiated, poorly differentiated, or undifferentiated histology

• Patient must have undergone diagnostic chest CT with or without contrast (IV contrast preferred) within 42 days prior to randomization. PET-CT may be used if the CT portion is of comparable diagnostic quality to a stand-alone CT. All disease must be assessed within 42 days prior to randomization

• Patient must have undergone FDG PET/CT of chest within 90 days prior to randomization

• Patient must not have evidence of hilar or mediastinal nodal involvement. Any patient with radiographically suspicious hilar or mediastinal nodes (including features such as non-calcified nodes with a short axis diameter > 1 cm, abnormal morphology, and/or elevated FDG avidity) must undergo cytologic sampling of suspicious nodes to rule out involvement prior to randomization. Mediastinal nodal sampling for other patients is optional. For cases in which the treating physician/multidisciplinary opinion is used to define nodes as "non-suspicious" (such as long-standing, stable enlarged nodes from other medical causes), the rationale must be clearly documented within the medical record

• Patient must have undergone history and physical examination within 28 days prior to randomization

• Patient must be medically or surgically inoperable as documented by the evaluating thoracic surgeon or multi-disciplinary tumor board consensus OR patient's unwillingness to undergo surgical resection must be clearly documented

• Patient must not have received any prior treatment for the current NSCLC diagnosis

• Patient must not have undergone prior radiation to overlapping regions of the chest that, in the opinion of the treatment physician, will interfere with protocol treatment

• Patient must not have received treatment with systemic immunostimulatory or immunosuppressive agents, including corticosteroids, within 14 days prior to randomization

• Patient must be >= 18 years old

• Patient must have Zubrod performance status of 0-2

• Patient must have adequate liver function defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional upper level of normal (IULN) within 28 days prior to randomization

• Patient must have adequate renal function defined as calculated creatinine clearance >= 30 mL/min using the following formula. The serum creatinine value used in the calculation must have been collected within 28 days prior to randomization

• Patient must have absolute neutrophil count (ANC), platelets, and hemoglobin measured within 28 days prior to randomization. The purpose of these tests is to collect baseline values to compare with on-treatment values

• Patient must have thyroid-stimulating hormone (TSH) measured within 28 days prior to randomization. The purpose of this test is to collect baseline values to compare with on-treatment values

• Patient must not have significant cardiovascular disease (New York Heart Association [NYHA] class II or greater)

• Patient must not have myocardial infarction within 90 days prior to randomization

• Patient must not have unstable arrhythmias or unstable angina

• Patient must not have known left ventricular ejection fraction (LVEF) < 40% within 28 days prior to randomization

  • NOTE: Assessment of LVEF by echocardiogram or multigated acquisition (MUGA) is not an eligibility requirement, but if a standard of care echocardiogram or MUGA was clinically indicated, the LVEF must not be < 40% within 28 days prior to randomization

• Patient must not have had an infection >= grade 3 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) within 28 days prior to randomization

• Patient must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed

• Patient must be tested for hepatitis B within 28 days prior to randomization. Patient must not have active (chronic or acute) hepatitis B virus (HBV) infection. Patients may have past or resolved HBV infection

  • Active HBV is defined as having a positive hepatitis B surface antigen (HBsAg) test
  • Past or resolved HBV is defined as having a negative HBsAG test and a positive total hepatitis B core antibody (HBcAb) test

• Patient must be tested for hepatitis C within 28 days prior to randomization. Patient must not have active hepatitis C virus (HCV) infection

  • Active HCV is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test

• Patient must have pulmonary function testing to include, at a minimum, forced expiratory volume in 1 second (FEV1) and Diffusing capability of carbon monoxide (DLCO) documented within 90 days prior to randomization

• Patients with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to randomization

• Patient must not have a history of clinically significant interstitial lung disease or evidence of active pneumonitis on the screening chest CT

• Patients must not have a prior or concurrent malignancy whose natural history or treatment has the potential (in the opinion of the treating physician) to interfere with the safety or efficacy assessment of the investigational regimen

• Patients must not be pregnant due to the potential teratogenic side effects of the protocol treatment. Women of reproductive potential and men must have agreed to use an effective contraception method for the duration of protocol treatment, and for 5 months (150 days) after the last dose of atezolizumab. A woman is considered to be of "reproductive potential" if she has had a menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding must be discontinued prior to randomization

• Patients of reproductive potential must have a negative serum pregnancy test within 14 days prior to randomization

• Patients must not have known active tuberculosis

• Patients must not have received a live, attenuated vaccine within 28 days prior to randomization

  • NOTE: All coronavirus disease 2019 (COVID-19) vaccines that have received Food and Drug Administration (FDA) approval or FDA emergency use authorization are acceptable

• Patients must not have a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab

• Patients must not have a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric antibodies, fusion proteins, or Chinese hamster ovary cell products or to any component of the atezolizumab formulation

• Patient must agree to have specimens submitted for translational medicine and banking

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

• Patients who can complete quality of life instruments in English, French, or Spanish must agree to complete the questionnaires at the protocol-specified time points

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