A Phase 3, Randomized, Double-Blind Study of Ociperlimab, an Anti-TIGIT Antibody, in Combination With Tislelizumab Compared to Pembrolizumab in Patients With Previously Untreated, PD-L1-Selected, and Locally Advanced, Unresectable, or Metastatic Non-Small Cell Lung Cancer

Prior treatment

• Infection (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before randomization, or patients who tested positive for COVID-19 antigen by a licensed test during screening. Note: Antiviral therapy is permitted for patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or > 2500 copies/mL) at Screening. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, (in Japan, defined as patients who are HBsAg-positive but asymptomatic), treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at Screening should have been treated for > 2 weeks before randomization.
• Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody. Patients receiving antivirals at Screening should have been treated for > 2 weeks before randomization.
• Any major surgical procedure ≤ 28 days before randomization. Patients must have recovered adequately from the toxicity and/or complications from the intervention before randomization.
• Prior allogeneic stem cell transplantation or organ transplantation.
• Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before randomization. b. Symptomatic pulmonary embolism diagnosed ≤ 28 days before randomization. c. Any history of acute myocardial infarction ≤ 6 months before randomization. d. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤ 6 months before randomization. e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before randomization. f. Any history of cerebrovascular accident ≤ 6 months before randomization. g. Uncontrolled hypertension that cannot be managed by standard antihypertension medications ≤ 28 days before randomization. For France only, specify: Systolic pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg on repeated measurements. h. Any episode of syncope or seizure ≤ 28 days before randomization.
• Was administered a live vaccine ≤ 28 days before randomization. Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-programmed cell death ligand 2 (PD L2), anti-TIGIT, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways.
• Concurrent participation in another therapeutic clinical study. Note: Concurrent participation in observational or noninterventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow up period can be enrolled in this study.
• Active leptomeningeal disease or uncontrolled, untreated brain metastasis. Note: Patients with a history of treated and, at the time of screening, stable central nervous system (CNS) metastases are eligible, provided that they meet all the following:  Brain imaging at Screening shows no evidence of interim progression, patient is clinically stable for at least 2 weeks and without evidence of new brain metastases.  Measurable and/or evaluable disease outside the CNS.  No ongoing requirement for corticosteroids as therapy for CNS disease; off steroids 3 days before randomization; anticonvulsants at a stable dose are allowed.  No stereotactic radiation or whole-brain radiation within 14 days before randomization.
• Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone [in Japan, prednisolone] or equivalent) or other immunosuppressive medication ≤ 14 days before randomization. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone [in Japan, prednisolone] or equivalent). b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption. c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen.
• Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks of intervention). Patients with symptomatic pleural effusion are excluded unless the patient undergoes a therapeutic thoracentesis or has had pleurodesis (more than 2 weeks prior) and has subsequently stable effusions.

Other illness

• Known history of HIV infection, or if HIV status is unknown, positive HIV test at Screening.
• A history of severe hypersensitivity reactions to other monoclonal antibodies or a history of hypersensitivity to the ingredients of tislelizumab or ociperlimab.
• Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening: a. Controlled Type I diabetes. b. Hypothyroidism (provided it is managed with hormone replacement therapy only). c. Controlled celiac disease. d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia). e. Any other disease that is not expected to recur in the absence of external triggering factors.
• History of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc. All patients must undergo an assessment of pulmonary function at Screening

Lab values

• Known mutations in a. EGFR gene (Note: Patients with nonsquamous NSCLC whose EGFR mutational status is unknown will be required to have a tissue-based EGFR test either locally or centrally, or endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-TBNA] based EGFR test locally at Prescreening.) Patients found to have EGFR-sensitizing mutations will be excluded. b. ALK fusion oncogene c. BRAF V600E d. ROS1 Note: If no targeted therapy approved by local health authority is available for BRAF V600E or ROS1 mutations, then these patients are eligible. ALK testing is required for patients with nonsquamous NSCLC in Korea, if ALK status is unknown.
• Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug or that will affect the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance with study conduct.
• Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia ≤ 14 days before randomization.

Age

• Any active malignancy ≤ 5 years before randomization except for the specific cancer under investigation in this study, those with a negligible risk of metastasis or death, and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, localized prostate cancer, or carcinoma in situ of the cervix or breast).

Other

• Women who are pregnant or are breastfeeding.

• Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
• Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drug, and must have a negative urine or serum pregnancy test ≤ 7 days before randomization.
• Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drug. • A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. • Males with known “low sperm counts” (consistent with “subfertility”) are not to be considered sterile for purposes of this study.
• Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).
• Histologically or cytologically documented locally advanced or recurrent NSCLC that is not eligible for curative surgery and/or definitive radiotherapy with or without chemoradiotherapy, or metastatic nonsquamous or squamous NSCLC.
• No prior systemic treatment for metastatic NSCLC.
• Agreement to provide archival tissue (formalin-fixed paraffin-embedded block containing tumor [preferred] or approximately 6 to 15 freshly cut unstained slides) or fresh biopsy (if archival tissue is not available) for central evaluation of PD-L1 levels and retrospective analysis of other biomarkers.
• Tumors with PD-L1 expressed in ≥ 50% tumor cells as determined centrally (or locally in the US and Japan).
• At least 1 measurable lesion as defined per RECIST v1.1. Note: A lesion in an area subjected to prior locoregional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since the therapy as defined by RECIST v1.1.
• ECOG Performance Status ≤ 1.
• Adequate organ function as indicated by the following laboratory values during screening: a. Patients must not have required blood transfusion or growth factor support ≤ 14 days before sample collection at Screening for the following:  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L  Platelets ≥ 75 x 109/L  Hemoglobin ≥ 90 g/L b. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation (Appendix 8). Note, for sites in France: Serum creatinine ≤ 1.5 x ULN and estimated glomerular filtration rate or estimated creatinine clearance ≥ 60 mL/min/1.73 m2 by CKD-EPI and Cockcroft and Gault equations, respectively (Appendix 8). c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome). d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN or < 5 x ULN if hepatic metastases present.