A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants With Untreated Locally Advanced Unresectable or Metastatic Renal Cell Carcinoma

Inclusion Criteria:

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1

• International Metastatic RCC Database Consortium (IMDC) risk intermediate (score of 1 or 2) or poor (score of 3-6)

• Measurable disease with at least one measurable lesion

• Histologically confirmed ccRCC with or without sarcomatoid features

• Negative for HIV, hepatitis B, or hepatitis C virus (HCV)

Exclusion Criteria:

• Pregnant or breastfeeding, or intention of becoming pregnant during the study orwithin 90 days after the final dose of tiragolumab, 4 months after the final dose oftobemstomig (RO7249669) and pembrolizumab, or for 1 week after the final dose ofaxitinib, whichever occurs last

• Inability to swallow a tablet or malabsorption syndrome

• Prior treatment for localized and/or metastatic RCC with systemic RCC-directedtherapy, including T-cell costimulating or immune checkpoint blockade therapies

• Ongoing use or anticipated need for treatment with a strong CYP3A4/5 inhibitor orinducer

• 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

• Uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiringcontinued use of bisphosphonate therapy or denosumab

• Symptomatic, untreated, or actively progressing central nervous system (CNS)metastases

• History of leptomeningeal disease

• Uncontrolled tumor-related pain

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently)

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• Uncontrolled hypertension

• Prior history of hypertensive crisis or hypertensive encephalopathy

• Significant cardiovascular/cerebrovascular disease within 3 months (12 months for UKparticipants) prior to randomization

• History of clinically significant ventricular dysrhythmias or risk factors forventricular dysrhythmias

• History of congenital QT syndrome

• Resting heart rate (HR) > 100 bpm (or clinically significant tachycardia)

• Stroke (including transient ischemic attack), myocardial infarction, or othersymptomatic ischemic event, or thromboembolic event (e.g., deep venous thrombosis [DVT], pulmonary embolism [PE]) within 3 months (12 months for UK participants)before randomization

• Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiringsurgical repair or recent peripheral arterial thrombosis) within 6 months prior toDay 1 of Cycle 1

• Tumors invading pulmonary blood vessels, cavitating pulmonary lesions or knownendobronchial disease

• Tumor invading the gastrointestinal (GI) tract, including abdominal ortracheoesophageal fistulas

• Evidence of abdominal free air not explained by paracentesis or recent surgicalprocedure

• Active peptic ulcer disease, acute pancreatitis, acute obstruction of the pancreaticor biliary duct, appendicitis, cholangitis, cholecystitis, diverticulitis, gastricoutlet obstruction

• Intra-abdominal abscess within 6 months before initiation of study treatment

• Clinical signs or symptoms of GI obstruction or requirement for routine parenteralhydration, parenteral nutrition, or tube feeding

• Evidence of bleeding diathesis or significant coagulopathy

• Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of studytreatment

• Clinically significant hematuria, hematemesis, hemoptysis of > 0.5 teaspoon (2.5 mL)of red blood, coagulopathy, or other history of significant bleeding (e.g.,pulmonary hemorrhage) within 3 months before initiation of study treatment

• Active or history of autoimmune disease or immune deficiency

• Treatment with systemic immunosuppressive medication within 2 weeks prior toinitiation of study treatment, or anticipation of need for systemicimmunosuppressive medication during study treatment

• Prior allogeneic stem cell or solid organ transplantation

• 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 of another primary malignancy other than RCC within 2 years prior toscreening, with the exception of malignancies with a negligible risk of metastasisor death (e.g., 5-year OS rate > 90%)

• Administration of a live, attenuated vaccine within 4 weeks before randomization oranticipation that such a live, attenuated vaccine will be required during the study

• Active tuberculosis (TB)

• Severe infection within 4 weeks prior to initiation of study treatment

• Participants with active Epstein-Barr virus (EBV) infection or known or suspectedchronic active EBV infection at screening

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment

• Known hypersensitivity to Chinese hamster *ovary cell products or to any componentof tobemstomig, tiragolumab, pembrolizumab, or axitinib