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

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. Treatment repeats every 21 days for 8 cycles. Starting on day 1 cycle 3, patients also undergo SBRT for 3-5 treatments over 1-3 weeks.

ARM B: Beginning 21 days after randomization, patients undergo SBRT for 3-5 treatments over 1-3 weeks.

After completion of study treatment, patients are followed up at weeks 18, 30, 42, and 54, every 6 months for 2 years, and then every 12 months for 2 years.

Study Design

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 multifocal tumors and pericardial involvement
• Disease must have one or more of the following high-risk features:
  • Tumor diameter >= 2 cm as assessed by diagnostic computed tomography (CT)
  • Tumor standard uptake value (SUV) max >= 6.2 as assessed by fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/CT
  • Moderately differentiated, poorly differentiated, or undifferentiated histology
• Patient must have undergone diagnostic chest CT with contrast (unless medically contraindicated) within 42 days prior to randomization. PET-CT may be used if the CT portion is of identical 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
• 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 < 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 RNA test
• Patient must have an forced expiratory volume in 1 second (FEV1) >= 700 cc and a diffusion capacity of the lung for carbon monoxide (DLCO) >= 5.5 m/min/mmHg from pulmonary function testing documented within 90 days prior to randomization
• Patient must not have known human immunodeficiency virus (HIV) unless he/she is on effective anti-retroviral therapy, has had at least one viral load test within 6 months prior to randomization, and had undetectable viral load at all viral load tests 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
• 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