This phase III trial studies how well chemotherapy and radiation therapy (chemoradiation) with or without atezolizumab works in treating patients with limited stage small cell lung cancer. Drugs used in chemotherapy, such as etoposide, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. 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. Giving chemoradiation with or without atezolizumab may work better in treating patients with limited stage small cell lung cancer.

PRIMARY OBJECTIVE:

I. To compare overall survival (OS) for patients with LS-SCLC treated with chemoradiation +/- atezolizumab.

SECONDARY OBJECTIVES:

I. To compare progression free survival (PFS) for patients with limited stage small cell lung cancer (LS-SCLC) treated with chemoradiation +/- atezolizumab.

II. To determine overall response rate (ORR), rates of local control, and distant metastases free survival with chemoradiation +/- atezolizumab.

III. To characterize immune mediated and non-immune mediated toxicity from chemoradiotherapy plus atezolizumab.

IV. To compare quality of life, as measured by the Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI), for patients undergoing chemoradiation +/- atezolizumab.

V. To evaluate the quality-adjusted survival, using scores from the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L), of chemoradiation +/- atezolizumab for patients with LS-SCLC.

VI. To characterize fatigue, as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS), following chemoradiation +/- atezolizumab.

VII. To determine the association of small cell lung cancer (SCLC) molecular subtypes with clinical outcomes.

EXPLORATORY OBJECTIVES:

I. To collect biospecimens at baseline, day 1 and 3 months after the end of chemoradiotherapy, to allow for future analyses.

II. To characterize patient-reported symptomatic toxicities measured by the Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE).

III. To characterize the concordance between tumor and circulating cell-free deoxyribonucleic acid (cfDNA)-determined molecular subtypes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive etoposide intravenously (IV) on days 1-3 and cisplatin IV or carboplatin IV on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) twice daily (BID) for approximately 3 weeks or once daily (QD) for approximately 6-7 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo blood specimen collection throughout the trial.

ARM II: Patients receive treatment as in Arm I. Patients also receive atezolizumab IV over 30-60 minutes on day 1 or 2 of each chemotherapy cycle. Cycles repeat every 3 weeks for 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients undergo blood specimen collection throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter.

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration

• Patients must have received one cycle of platinum/etoposide chemotherapy pre-registration (prior to study entry). Study registration must be within 21 days from day 1 of the pre-registration cycle of chemotherapy.

• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required pre-registration cycle of platinum/etoposide chemotherapy

• Minimal staging requirements include:

  • History/physical examination within 30 days prior to registration

  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 60 days prior to registration

  • CT chest and CT abdomen with IV contrast (unless contraindicated based on kidney function) within 60 days prior to registration; magnetic resonance imaging (MRI) abdomen with IV contrast allowed in place of CT abdomen

    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy

  • MRI scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration

• Absolute neutrophil count (ANC) >= 1,500/cells/mm^3 (prior to pre-registration cycle)

• Platelet count >= 100,000 cells/mm^3 (prior to pre-registration cycle)

• Hemoglobin >= 9 g/dL (prior to pre-registration cycle)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (prior to pre-registration cycle)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x ULN (prior to pre-registration cycle)

• Adequate renal function within 30 days prior to registration defined as follows: Creatinine clearance >= 30 mL/min by the Cockcroft-Gault (C-G) equation

• Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging

• Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

• Hepatitis B/C testing prior to enrollment for patients that have not been tested before. Note: This is required even if the patient has never shown or had symptoms of hepatitis

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria:

• Definitive clinical or radiologic evidence of metastatic disease

• Definitive surgical resection of small cell lung cancer

• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible)

• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable

• Any prior atezolizumab or other immunotherapy agent

• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs)

• Patients with cytologically positive pleural or pericardial fluid are not eligible

• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger

• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

• History of allogeneic organ transplant

• History of primary immunodeficiency

• Severe, active co-morbidity defined as follows:

  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease

  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

  • Active tuberculosis

  • Active hepatitis B (chronic or acute) or hepatitis C infection. Note that if hepatitis status is unknown, hepatitis B/C testing is required

    • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible
    • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test.)

  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL)

  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months

  • Transmural myocardial infarction within the last 3 months

  • Clinically significant interstitial lung disease

• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

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