Phase II Trial of Single Agent Belzutifan or Pembrolizumab Versus Combination as Neoadjuvant Therapy in Clear Cell Renal Cell Carcinoma (BLAZE)

To learn if belzutifan alone, pembrolizumab alone, or belzutifan and pembrolizumab in combination given before a total or partial nephrectomy (surgery to remove all or part of a kidney) can help to control locally advanced ccRCC.

Inclusion Criteria: * Biopsy proven clear cell renal cell carcinoma (ccRCC). a. Extra tissue should be submitted if available for correlative analysis. Formalin-fixed paraffinembedded (FFPE) tissue blocks are preferred to slides. Details pertaining to tumor tissue submission can be found in the Lab Procedures Manual. * Has intermediate-high risk, high risk, or M1 ccRCC as defined by the following pathological tumor-node metastasis and tumor grading: Intermediate-high risk ccRCC\* 1. pT2 (by radiographic/size criteria), Grade 4 or with sarcomatoid/rhabdoid features (on biopsy), N0, M0 2. pT3 (presence of tumor thrombus, perinephric and/or sinus fat invastion by imaging), any grade, N0, M0 High-risk ccRCC\* 3. pT4, any g.rade, N0, M0 4. pT, any stage, any grade, N+, M0 M1 RCC participants who present with the primary kidney tumor, but also solid, isolated, soft tissue metastases that are planned to be completely resected at the time of nephrectomy are eligible (e.g. metastasis to ipsilateral adrenal gland). * NOTE: Fuhrman Tumor Grade and/or WHO/ISUP Tumor Grade are required for all subjects entering the study. • Evaluated by urology and approved as candidates for nephrectomy. • Age ≥18 years and consent to participation. • Performance status of 0-1 per Zubrod/Eastern Cooperative Oncology Group \[ECOG\] scale. • Absence of distant metastases on imaging of chest, abdomen and pelvis within 42 days of enrollment (by CT, MRI, or PET imaging). Brain imaging is not required unless clinical suspicion per the treating provider. • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. • Screening laboratory criteria include the following: a. ANC ≥1000, PLT ≥ 75, Hgb ≥9 (transfusion allowed if Hgb \< 1.5 or = to upper limit of normal • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. • Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (see below) prior to study entry and for the duration of study participation, including for 120 days after the last dose of pembrolizumab and 30 days after the last dose of belzutifan. WOCBP will be required to have a negative pregnancy test prior to cycle 1 day 1 of treatment, ≤24 hours prior to first dose of treatment. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \ 1. A pulse oximeter reading \