Testing the Addition of the Drug Atezolizumab to the Usual Radiation Treatment for Patients With Early Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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. To assess quality of life as measured by the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)-30 and EORTC-QLQ- Lung Cancer (LC)13 between the arms. 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.

Official Title
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A Randomized Phase III Trial of Induction/Consolidation Atezolizumab (NSC #783608) + SBRT Versus SBRT Alone in High Risk, Early Stage NSCLC

Conditions
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Lung Non-Small Cell Carcinoma, Stage I Lung Cancer AJCC v8, Stage II Lung Cancer AJCC v8

Intervention / Treatment
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* Drug: Atezolizumab
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Other: Fludeoxyglucose F-18
* Procedure: Positron Emission Tomography
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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 a board certified 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (atezolizumab, SBRT)<br>Patients receive atezolizumab 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 QD over 1-3 weeks. Patients undergo FDG-PET/CT during screening. Patients undergo blood sample collection and CT scans throughout the trial. | Drug: Atezolizumab<br>* Given IV<br>* Other names: Tecentriq;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Undergo FDG PET/CT<br>* Other names: Fluorodeoxyglucose F18;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|
| Active Comparator: Arm B (SBRT)<br>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. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Other: Fludeoxyglucose F-18<br>* Undergo FDG PET/CT<br>* Other names: Fluorodeoxyglucose F18;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Will compare overall survival between patients with inoperable, T1, T2, limited T3, N0M0 (early stage) non-small cell lung cancer randomized to stereotactic body radiation therapy with or without atezolizumab. Will be evaluated using the method of Kaplan-Meier. For point estimates at landmark times, the associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model and estimated using a stratified Cox regression model. | From date of randomization to date of death due to any cause, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Will be evaluated using the method of Kaplan-Meier. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model and estimated using a stratified Cox regression model. | From date of randomization to date of first documentation of progression or death due to any cause, assessed up to 5 years | 
| Incidence of adverse events | This study will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for toxicity and serious adverse event reporting. | Up to 5 years |