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, patientsmust have PDL1 TPS >50%, as determined by an FDA-approved test.

• Patients must have asymptomatic brain metastases with at least one untreatedevaluable (per RANO-BM) brain metastasis of 5 mm or more. A growing lesionpreviously treated with whole brain radiotherapy is acceptable given the lowerincidence of radiation necrosis. Lesions previously treated with SRS may not be usedas 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 earlystage or locoregionally advanced NSCLC is permitted, if completed more than 12months prior to initiation of study treatment.

• Prior radiation with palliative intent in the metastatic setting to non-CNS lesionsis 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 positiveare 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 HBVDNA test must also be performed to determine if the patient has an HBV infection,which would render the patient ineligible. Patients receiving treatment withanti-viral therapy for HBV are excluded.

• Negative hepatitis C antibody. If positive, an HCV RNA test must also be performedto determine if the patient has an HCV infection, which would render the patientineligible.

• Availability of a representative tumor specimen for exploratory biomarker research.

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual 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 oftiragolumab, 5 months after the final dose of atezolizumab, and 6 months after thefinal 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 amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) oranother cause as determined by the investigator (e.g., Müllerian agenesis). Perthis definition, a woman with a tubal ligation is considered to be ofchildbearing potential. The definition of childbearing potential may be adaptedfor alignment with local guidelines or regulations.

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone-releasing intrauterine devices, and copperintrauterine devices.

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods ofcontraception. If required per local guidelines or regulations, locallyrecognized adequate methods of contraception and information about thereliability of abstinence will be described in the local Informed Consent Form.

• Women who would like to become pregnant after study treatment discontinuation shouldseek advice on oocyte cryopreservation prior to initiation of study treatmentbecause of the possibility of irreversible infertility due to treatment withcisplatin and carboplatin.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom, and agreement to refrain from donating sperm, as defined below:

• With a female partner of childbearing potential, men who are not surgicallysterile must remain abstinent or use a condom plus an additional contraceptivemethod that together result in a failure rate of < 1% per year during thetreatment period, for 90 days after the final dose of tiragolumab, and for 6months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatinor cisplatin. Men must refrain from donating sperm during this same period.

• With a pregnant female partner, men must remain abstinent or use a condomduring 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 theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods ofcontraception. If required per local guidelines or regulations, locallyrecognized adequate methods of contraception and information about thereliability of abstinence will be described in the local Informed Consent Form.

• Men who would like to father a child after study treatment initiation should beadvised regarding the conservation of sperm prior to treatment because of thepossibility of irreversible infertility resulting from chemotherapies used in thisstudy.

• Women of childbearing potential must have a negative serum pregnancy test resultwithin 14 days prior to initiation of study treatment.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Symptoms related to brain metastases requiring CNS radiation ≤ 2 weeks of treatmentinitiation 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 notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barrésyndrome, or multiple sclerosis, with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroidreplacement hormone are eligible for the study.

• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only topicalcorticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high potency or oral corticosteroidswithin the previous 12 months.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan. History ofradiation 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 orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina.

• Major surgical procedure, other than for diagnosis, within 4 weeks prior toinitiation of study treatment, or anticipation of need for a major surgicalprocedure during the study.

• History of malignancy other than NSCLC within 2 years prior to screening, with theexception 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, orsevere pneumonia.

• Prior allogeneic stem cell or solid organ transplantation.

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications.

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during atezolizumabtreatment 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 priorto initiation of study treatment, or anticipation of need for systemicimmunosuppressive medication during study treatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof 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, orlow-dose corticosteroids for orthostatic

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to atezolizumab or other agents used in study.

• History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins.

• Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab or tiragolumab formulation.

• Pregnancy or breastfeeding, or intention of becoming pregnant during studytreatment, within 90 days after the final dose of tiragolumab, 5 months after thefinal dose of atezolizumab, or 6 months after the final dose of pemetrexed,gemcitabine, paclitaxel, carboplatin, or cisplatin o Women of childbearing potentialmust have a negative serum pregnancy test result within 14 days prior to initiationof study treatment.