A Study to Evaluate the Safety, Tolerability, and Efficacy of Pumitamig Alone or in Combination With Other Agents in Participants With Advanced Renal Cell Carcinoma (RCC) (ROSETTA RCC-208)

Prior treatment

• Participants must not have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of Cycle 1 Day1 (C1D1).
• Participants must not have a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism within 6 months prior to C1D1.
• Participants must not have had a major surgery or trauma within 28 days prior to C1D1.
• For Part 2D and 2E: Receiving ongoing concomitant treatment with sensitive substrates of CYP3A4, CYP2C8, CYP2C9, or CYP2C19 with narrow therapeutic indices within 5 half-lives of the concomitant treatment or up to 28 days, whichever is shorter, prior to randomization.
• For Part 2D and 2E: Receiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, or moderate or strong CYP3A4 inhibitors within 5 half-lives of the concomitant treatment, or up to 28 days, whichever is shorter, prior to randomization.

Other illness

• Participants must not have a history of interstitial lung disease or pneumonitis.
• Participants must not have evidence of major coagulation disorders.
• Participants must not have a history of abdominal fistula or gastrointestinal (GI) perforation within 6 months.
• For Part 2D and 2E: Presence of significant pulmonary disease/condition (eg, chronic obstructive pulmonary disease, pleural effusion, etc) that, in the opinion of the Investigator, could put participant at increased risk from study intervention or impact interpretation of safety data.

Lab values

• Participants must not have significant cardiovascular disease, such as myocardial infarction, unstable angina, arterial thrombosis, cerebrovascular accident within 6 months prior to C1D1, uncontrolled hypertension (≥ 150 systolic, ≥ 90 diastolic mm Hg) despite optimal medical management, left ventricular ejection fraction (LVEF) \<50% (for Part 2D and 2E) or congenital long QT syndrome.
• Participants must not have a urine protein ≥ 2+ on dipstick or urinalysis at baseline and confirmed proteinuria ≥ 1 g/24 hours or urine protein-creatinine ratio (UPCR) \> 1000 mg/g.

Other

• Participants must not have any untreated known CNS metastases.
• Participants must not have an uncontrolled pleural or pericardial effusion requiring recurrent therapeutic drainage procedures.
• For Part 2D and 2E: Has hypoxia defined by a pulse oximeter reading \< 92% at rest or requires intermittent or chronic supplemental oxygen.
• For Part 2D and 2E: Exercise-induced desaturation on a 6-minute walk test, defined as a blood oxygen saturation by pulse oximetry ≤ 88%.
• Other protocol-defined Inclusion/Exclusion criteria apply.

• Participants must have a histologically confirmed diagnosis of locally advanced, unresectable (not amenable to curative surgery or radiation therapy) or metastatic Renal Cell Carcinoma (RCC).
• Participants must have clear cell RCC (ccRCC) or non-clear cell RCC (nccRCC) may be enrolled in Part 1. Note: Part 2 may only enroll participants with ccRCC.
• Participants may have favorable, intermediate or poor risk disease categories.
• Participants must not have received prior systemic therapy for metastatic RCC, with the following exceptions:
  • One prior adjuvant or neoadjuvant therapy for completely resectable RCC is allowed if such therapy did not include an agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.
• For Part 1A participants: Prior systemic therapy in the metastatic setting is allowed if the participant has not received any therapy targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) (e.g., ipilimumab).
• For Part 1B participants: Prior systemic therapy in the metastatic setting is allowed if the participant has not received prior treatment with cabozantinib.
• For Parts 2D and 2E: Prior treatment with a HIF-2α inhibitor or other agent that targets the HIF-2α pathway is not allowed.
  • \- Participants must have measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.