Eligibility

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 or within 90 days after the final dose of tiragolumab, 4 months after the final dose of tobemstomig (RO7249669) and pembrolizumab, or for 1 week after the final dose of axitinib, whichever occurs last
• Inability to swallow a tablet or malabsorption syndrome
• Prior treatment for localized and/or metastatic RCC with systemic RCC-directed therapy, including T-cell costimulating or immune checkpoint blockade therapies
• Ongoing use or anticipated need for treatment with a strong CYP3A4/5 inhibitor or inducer
• 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
• Uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiring continued 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 recurrent drainage 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 UK participants) prior to randomization
• History of clinically significant ventricular dysrhythmias or risk factors for ventricular dysrhythmias
• History of congenital QT syndrome
• Resting heart rate (HR) > 100 bpm (or clinically significant tachycardia)
• Stroke (including transient ischemic attack), myocardial infarction, or other symptomatic 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 requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1
• Tumors invading pulmonary blood vessels, cavitating pulmonary lesions or known endobronchial disease
• Tumor invading the gastrointestinal (GI) tract, including abdominal or tracheoesophageal fistulas
• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
• Active peptic ulcer disease, acute pancreatitis, acute obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, diverticulitis, gastric outlet obstruction
• Intra-abdominal abscess within 6 months before initiation of study treatment
• Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, 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 study treatment
• 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 to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
• Prior allogeneic stem cell or solid organ transplantation
• 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 another primary malignancy other than RCC 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%)
• Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation 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 suspected chronic active EBV infection at screening
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Known hypersensitivity to Chinese hamster *ovary cell products or to any component of tobemstomig, tiragolumab, pembrolizumab, or axitinib