Background: Renal cell carcinoma (RCC) has a biologic propensity for vascular invasion leading to a venous tumor thrombus (VTT) in the renal vein or inferior vena cava (IVC) in up to 25% of cases. RCC with VTT is a poor prognostic factor for cancer-related mortality. Additionally, depending on the tumor burden and extent of the tumor thrombus (TT), patients can become symptomatic from the VTT, affecting patients’ quality of life. The current standard of care for RCC with an IVC TT is to undergo a radical nephrectomy with an IVC thrombectomy which may be associated with high surgical morbidity and mortality. We hypothesize that the combination of PEMBRO and AXI given in the neoadjuvant setting will decrease the IVC TT burden. The KEYNOTE-426 trial evaluated the combination of PEMBRO and AXI in the metastatic setting which showed an objective response rate of 59.3%. Thus, it is reasonable to consider a response in the overall burden of disease, inclusive of the VTT. This decrease in size of the VTT can potentially lead to decreased surgical complications, improve patient-related outcomes, and improve progression-free survival (PFS) and overall survival (OS). Methods: This single-center, open-label, single-arm phase II trial is enrolling patients with clear cell RCC that demonstrate IVC TT. The primary endpoint is the IVC TT response (change in size) after neoadjuvant PEMBRO and AXI. The extent of IVC TT will be measured by the Mayo classification and cross-sectional dimensions. Secondary endpoints include surgical complications/morbidity per Clavien-Dindo classification, 1-year PFS, 1-year OS, and safety of PEMBRO and AXI. Correlative analysis of pre and post operative tumor samples will also be performed. Patients will receive the combination of PEMBRO 200 mg intravenously and AXI 5 mg orally twice daily every 21 days for 4 cycles. A radiographic assessment will be performed at baseline and after up to 12 weeks (4 cycles) of therapy to evaluate the primary endpoint of IVC TT response. Patients will undergo a definitive surgery per treating urologist within 2 weeks (+/- 7 days) after this evaluation. Patients will have at least cT3b tumor with or without lymph node or distant metastases and a biopsy confirming a component of clear cell RCC. The study will include patients who are candidates for upfront surgery as determined by their treating urologist. A Simon’s two-stage design will be utilized with the first stage enrolling 9 subjects. If there are zero responses, the trial will be stopped. If there are 3 or more patients that are not able to undergo surgery due to treatment-related adverse events, enrollment will be paused. If neither of these occur, we will enroll 8 additional subjects, rejecting the null hypothesis of an IVC response in only 5% of patients if we observe at least 3 of 17 patients with a measured reduction from baseline size of the TT. Clinical trial information: NCT05969496.