Testing the Addition of Radiation Therapy to the Usual Immune Therapy Treatment (Atezolizumab) for Extensive Stage Small Cell Lung Cancer, The RAPTOR Trial

Inclusion Criteria:

• Any confirmation (cytologic, histologic, or pathologic) of extensive stage smallcell lung cancer at any site, either primary or metastases

• Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography [PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging [MRI] optional per treating physician); atezolizumab should continue throughrandomization. Patients must be randomized within 9 weeks of last dose ofetoposide/platinum (if not receiving PCI) or 6 weeks from completion of prophylacticcranial irradiation (PCI)

• NOTE: Patients must have at least 3 cycles of E/P plus atezolizumab. They canhave one cycle of induction E/P without concurrent atezolizumab if unable toreceive concurrent E/P combined with atezolizumab for all cycles of inductiontherapy

• Patients must have measurable disease (per Response Evaluation Criteria in SolidTumors [RECIST]) and 3 or fewer observable liver metastases and no evidence ofprogressive disease (per RECIST) at time of enrollment

• At time of enrollment after induction E/P chemotherapy and atezolizumab, if there isa pleural effusion, patients will be eligible if thoracentesis is cytologicallynegative or if pleural fluid is too small a volume to effectively sample bythoracentesis and does not show increased metabolic activity on CT/PET imaging

• Appropriate stage for study entry based on the following diagnostic workup:

• History/physical examination within 14 days prior to registration;

• Imaging within 42 days prior to registration to include:

• MRI brain with contrast or CT brain with contrast

• CT chest, abdomen and pelvis or whole body PET/CT scan any time after thefourth cycle of chemotherapy and prior to registration

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 14 daysprior to registration

• Absolute neutrophil count (ANC) >= 1,000/cells/mm^3 (within 14 days prior toregistration)

• Platelets >= 75,000 cells/mm^3 (within 14 days prior to registration)

• Hemoglobin >= 8 g/dL (within 14 days prior to registration)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior toregistration)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN (AST and/or ALT =< 5 ULN for patients with liver involvement) (within 14days prior to registration)

• Alkaline phosphatase =< 2.5 x ULN (=< 5 ULN for patients with documented liverinvolvement or bone metastases) (within 14 days prior to registration)

• Adequate renal function = Creatinine clearance >=40 mL/min by the Cockcroft-Gault (C-G) equation: (within 14 days prior to registration)

• Upfront radiation therapy of symptomatic metastatic site is permissible if causingsymptoms such as pain or impending fracture

• Patients with brain metastases are eligible after receiving whole brain radiationbefore enrollment (anytime during induction systemic therapy). Whole brain radiationcan be delivered with hippocampal sparing or 3-D conformal technique. Patients withirradiated brain metastases are eligible if they are clinically stable from aneurological standpoint after completing radiotherapy (e.g. not having uncontrolledseizures) and do not require use of steroids above a dose of 10 mg of prednisonedaily

• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration.

• Note: Women will be considered post-menopausal if they have been amenorrheicfor 12 months without an alternative medical cause. The following age-specificrequirements apply:

• Women < 50 years of age would be considered post-menopausal if they havebeen amenorrheic for 12 months or more following cessation of exogenoushormonal treatments and if they have luteinizing hormone andfollicle-stimulating hormone levels in the post-menopausal range for theinstitution or underwent surgical sterilization (bilateral oophorectomy orhysterectomy)

• Women >= 50 years of age would be considered post-menopausal if they havebeen amenorrheic for 12 months or more following cessation of allexogenous hormonal treatments, had radiation-induced menopause with lastmenses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy,bilateral salpingectomy or hysterectomy)

• Patients positive for human immunodeficiency virus (HIV) on effectiveanti-retroviral therapy with undetectable viral load within 6 months and a stableregimen of highly active anti-retroviral (HAART) HIV-positive patients must have norequirement for concurrent antibiotics or antifungal agents for the prevention ofopportunistic infections

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

Exclusion Criteria:

• Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastaticsites detectable after induction systemic therapy. Each visible bone metastasis onradiographic scan counts as one site

• Patients with a concurrent malignancy whose natural history or treatment has thepotential to interfere with the safety or efficacy assessment of the investigationalregimen with atezolizumab or radiation

• Prior radiotherapy in the thorax that would result in overlapping RT fields, unlessthe overlapping fields meet acceptable dose constraints for normal tissue

• Active autoimmune disease, including, but not limited to: systemic lupuserythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g. Crohn's,ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome;Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiplesclerosis; vasculitis; or glomerulonephritis.

• If the autoimmune disease is not active for over 3 years and the patient is notreceiving immunosuppressive treatment such as methotrexate or steroids above adose equivalent to 10 mg prednisone daily, the patient is eligible.

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone are eligible

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

• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo withdermatologic manifestations are excluded only if they have active disease withacute exacerbation and on immunosuppressive medications within the 12 monthsprior to enrollment. They are eligible otherwise.

• Severe, active co-morbidity defined as follows:

• Any other diseases, metabolic dysfunction, physical examination finding, orclinical laboratory finding giving reasonable suspicion of a disease orcondition that contraindicates the use of an investigational drug or that mayaffect the interpretation of the results or render the patient at high riskfrom treatment complications;

• Active tuberculosis;

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

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible

• Patients positive for hepatitis C virus (HCV) antibody are eligible onlyif polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have apositive HCV antibody test)

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

• Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroidtherapy 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 hospitalizationwithin the last 3 months;

• History of recent myocardial infarction within 6 months prior to registration.

• Clinically significant interstitial lung disease

• Pregnancy: Administration of atezolizumab may have an adverse effect on pregnancyand poses a risk to the human fetus, including embryo-lethality. Women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study treatment, and for 5 months (150 days) after the last dose ofstudy agent. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately

• Women who are breastfeeding and unwilling to discontinue

• History of allogeneic organ transplant

• Patients who have had immunotherapy-induced pneumonitis