This phase I trial studies the side effects and best dose of atezolizumab that can be given together with stereotactic body radiation therapy (SBRT) in treating patients with stage I non-small cell lung cancer that cannot be removed by surgery. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Stereotactic body radiation therapy is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may kill more tumor cells and cause less damage to normal tissue. Giving atezolizumab together with stereotactic body radiation therapy may kill more tumor cells and be a better treatment for non-small cell lung cancer that cannot be removed by surgery.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of MPDL3280A (atezolizumab) that can be given with stereotactic ablative radiotherapy (SAR) (stereotactic body radiation therapy) in patients with inoperable stage I non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To characterize the safety profile of this regimen using CTCAE v4 (Common Toxicity Criteria for Adverse Events version 4).

II. To provide preliminary efficacy data of the combination as determine by objective response rate and disease free survival using RECIST 1.1 (Response Evaluation Criteria for Solid Tumors) and Immune Related RECIST (irRECIST).

TERTIARY OBJECTIVES:

I. To analyze serial blood for change in cytokine signatures, fluorescence activated cell sorting (FACS) and immunophenotyping of peripheral blood mononuclear cells (PBMCs) and tumor infiltrating immune cells.

II. To evaluate pre and post treatment tumor tissue (if available) for programmed cell death-ligand 1 (PD-L1) and other immune proteins in the tumor and tumor microenvironment and for molecular profiling in a subset of patient samples.

III. To discover biomarkers of response from the data obtained.

OUTLINE: This is a dose-escalation study of atezolizumab.

DOSE ESCALATION PHASE: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Within 24-48 hours after receiving atezolizumab, patients also undergo 4-5 fractions of stereotactic body radiation therapy over days 1-5 of course 3.

EXPANSION PHASE: Patients receive atezolizumab IV over 30-60 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Within 24-48 hours after receiving atezolizumab, patients also undergo 4-5 fractions of stereotactic body radiation therapy over days 1-5 of course 3.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, and then every 6 months for 3 years.

Inclusion Criteria:

• Histologically proven stage I NSCLC =< 5 cm diameter

• One or more high-risk features identified:

  • Tumor diameter >= 2 cm
  • Tumor standardized uptake value maximum (SUVmax) >= 6.2
  • Moderately, poorly differentiated or undifferentiated histology

• Evaluable disease per RECIST 1.1

• Patients must be medically or surgically inoperable as determined by a physician OR unwilling to undergo surgical resection

• All patients must have an forced expiratory volume in 1 second (FEV1) >= 700cc

• All patients must have a carbon monoxide diffusing capability test (DLCO) >= 5.5 m/min/mmHg

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2

• Life expectancy >= 12 months

• Absolute neutrophil count (ANC) > 1500 cells/uL

• White blood cell count (WBC) > 2500/uL

• Lymphocyte count > 500/uL

• Platelet count > 100,000/uL

• Hemoglobin > 9 g/dL

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) with alkaline phosphatase =< 2.5 x ULN OR AST and ALT =< 1.5 x ULN, with alkaline phosphatase > 2.5 x ULN

• Serum bilirubin =< 1.0 x ULN

• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.5 x ULN (for patients on anticoagulation they must be receiving a stable dose for at least 1 week prior to enrollment)

• Creatinine clearance > 30 mL/min by Cockcroft-Gault formula

• No history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs)

• No other active malignancy

• Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible

• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible

• Archival tumor sample available; tissue from an fine-needle aspiration (FNA) is allowed but tumor tissue from a core needle biopsy is preferred

• For female patients of childbearing potential and male patients with partners of childbearing potential agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of MPDL3280A

• Signed informed consent

• Ability to comply with the protocol

Exclusion Criteria:

• Uncontrolled concomitant disease
• Significant cardiovascular disease (New York Heart Association Class [NYHA] class II or greater); myocardial infarction within 3 month prior to randomization, unstable arrhythmias, unstable angina or a patient with a known left ventricular ejection fraction (LVEF) < 40%
• Severe infection within 4 weeks prior to enrollment
• Active tuberculosis
• Oral or IV antibiotics within 2 weeks or 5 half-lives prior to enrollment
• History of autoimmune disease
• Positive for human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface antigen [HBsAg] reactive), or hepatitis C virus (hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is detected)
• History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia
• Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrollment
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within past 4 weeks or 5 half-lives whichever is shorter
• Pregnant and/or lactating women