Tiragolumab and Atezolizumab in Patients With Non-squamous Non-small Cell Lung Cancer (NSCLC) and Untreated Brain Metastases

Inclusion Criteria: * Patients must have histologically or cytologically confirmed non-squamous NSCLC. * In patients treated with the combination of tiragolumab and atezolizumab, patients must have PDL1 TPS \>50%, as determined by an FDA-approved test. * Patients must have asymptomatic brain metastases with at least one untreated evaluable (per RANO-BM) brain metastasis of 5 mm or more. A growing lesion previously treated with whole brain radiotherapy is acceptable given the lower incidence of radiation necrosis. Lesions previously treated with SRS may not be used as target lesions. o Patients are not required to have measurable disease outside the CNS per RECIST 1.1. * Prior chemotherapy, immunotherapy or radiation given with curative intent in early stage or locoregionally advanced NSCLC is permitted, if completed more than 12 months prior to initiation of study treatment. * Prior radiation with palliative intent in the metastatic setting to non-CNS lesions is permitted (no wash-out period). * Age ≥18 years. * ECOG performance status ≤ 1. * Life expectancy ≥12 weeks. * Patients must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥1,500/mcL * Platelets ≥100,000/mcL * Total bilirubin ≤ institutional upper limit of normal (ULN) * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN * Creatinine Clearance (CrCl) ≥45 mL/min/1.73 m2 * No known history of HIV, with the following exception: patients who are HIV positive are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/µL, and have an undetectable viral load. * Negative hepatitis B surface antigen (HBsAg) test at screening. If positive, an HBV DNA test must also be performed to determine if the patient has an HBV infection, which would render the patient ineligible. Patients receiving treatment with anti-viral therapy for HBV are excluded. * Negative hepatitis C antibody. If positive, an HCV RNA test must also be performed to determine if the patient has an HCV infection, which would render the patient ineligible. * Availability of a representative tumor specimen for exploratory biomarker research. * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception: * Women must remain abstinent or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, and 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin. * A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. * Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. * Women who would like to become pregnant after study treatment discontinuation should seek advice on oocyte cryopreservation prior to initiation of study treatment because of the possibility of irreversible infertility due to treatment with cisplatin and carboplatin. * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: * With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period, for 90 days after the final dose of tiragolumab, and for 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin or cisplatin. Men must refrain from donating sperm during this same period. * With a pregnant female partner, men must remain abstinent or use a condom during the treatment period for 90 days after the final dose of tiragolumab, and for 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin to avoid exposing the embryo. * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. * Men who would like to father a child after study treatment initiation should be advised regarding the conservation of sperm prior to treatment because of the possibility of irreversible infertility resulting from chemotherapies used in this study. * Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Symptoms related to brain metastases requiring CNS radiation ≤ 2 weeks of treatment initiation are exclusionary. Steroids greater than prednisone 10 mg/d or equivalent, or anti-epileptic therapy ≤ 2 weeks of treatment initiation are exclusionary. * Prior systemic therapy for metastatic disease is not allowed. * Patients whose tumors harbor oncogenic drivers with an approved 1st line therapy (e.g. EGFR, ALK, and ROS1 alterations) are excluded. * Patients who are receiving any other investigational agents. * Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study. * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: * Rash must cover \< 10% of body surface area * Disease is well controlled at baseline and requires only topical corticosteroids * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months. * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis or fibrosis in a radiation field is permitted. * History of leptomeningeal disease. * Active tuberculosis. * Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. * Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study. * History of malignancy other than NSCLC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate ≥ 90%). * Severe infection within 2 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. * Prior allogeneic stem cell or solid organ transplantation. * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. * Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab. * Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids in excess of prednisone 10 mg/d or equivalent, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study. * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic * History of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab or other agents used in study. * History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. * Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation. * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment, within 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, or 6 months after the final dose of pemetrexed, gemcitabine, paclitaxel, carboplatin, or cisplatin o Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.